0A4F4F9BD490A749D5437F821CF06DF1
Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) (1997)
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/3cc1aen_en.pdf
http://leaux.net/URLS/ConvertAPI Text Files/914915A106D37815B377FCA45510948A.en.txt
Examining the file media/Synopses/914915A106D37815B377FCA45510948A.html:
This file was generated: 2020-07-15 06:40:43
| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / nomad
Searching for indicator nomads:
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p.000012: insert/summary of product characteristics for an a pproved product) (see note for guidance on Clinical
p.000012: Safety Data Management: Definitions and Standards for Expedited Reporting ).
p.000012:
p.000012: 1.61 Vulnerable Subjec ts
p.000012: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
p.000012: expectation, whether justified or not, of benefits associated with participation, or of a
p.000012: retaliatory response from senior members of a hierarchy in case of refusal to participate.
p.000012: Examples are members of a group with a hierarchical structure, such as medical, p harmacy, dental, and
p.000012: nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
p.000012: industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
p.000012: include patients with in curable diseases, persons in nur s i n g homes, unemployed or
p.000012: impoverished persons, patients in emergency situations, ethnic minority groups, homeless
p.000012: persons, nomads, refugees, minors, and those incapable of giving consent.
p.000012:
p.000012: 1.62 Well-being ( of the trial subjects)
p.000012: The physical and mental integrity of the subjects participating in a clinical trial.
p.000012:
p.000012:
p.000012:
p.000012: 2. THE PRINCIPLES OF ICH GCP
p.000012: 2.1 Clinical trials should be conducted in accordance with the ethical principles that
p.000012: have their origin in the Declaration of Helsinki, and that are consistent with GCP and the
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
p.000012: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000012: considerations and should prevail over interests of science and society.
p.000012: 2.4 The available nonclinical and clinical information on an investigational product
p.000012: should be adequate to support the proposed clinical trial.
p.000012:
p.000012:
p.000013: 13
p.000013:
p.000013: ■ 3CC1a _____________________________________________________________
p.000013:
p.000013:
p.000013:
p.000013: 2.5 Clinical trials should be scientifically sound, and described in a clear,
p.000013: detailed protocol.
...
Political / political affiliation
Searching for indicator party:
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p.000006: applicable regulatory requirements.
p.000006:
p.000006: 1.16 Confid en tiality
p.000006: Prevention of disclosure, to other than authorised individuals, of a sponsor's proprietary
p.000006: information or of a subject’s identity.
p.000006:
p.000006: 1.17 Contract
p.000006: A written, dated, and signed agreement between two or more involved parties that sets out any
p.000006: arrangements on delegation and distribution of tasks and obligations and, i f
p.000006: appropriate, on financial matters. The protocol may serve as the basis of a contract.
p.000006:
p.000006: 1.18 Co-ordinating Committee
p.000006: A committee that a sponsor may organise to co-ordinate the conduct of a multicentre trial.
p.000006:
p.000006:
p.000006: 1.19 Co-ordinating Investigator
p.000006: An investigator assigned the responsibility for the co-ordination of investigators at different centres
p.000006: participating in a multicentre trial.
p.000006:
p.000006: 1.20 Contract Research Organisation (CRO)
p.000006: A person or an organisation (commercial, academic, or other) contracted by the sponsor to perform
p.000006: one or more of a sponsor’s trial-related duties and functions.
p.000006:
p.000007: 7
p.000007:
p.000007: ■ 3CC1a _____________________________________________________________
p.000007:
p.000007:
p.000007:
p.000007: 1.21 Direct Access
p.000007: Permission to examine, analyse, verify, and reproduce any records and reports that are
p.000007: important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory
p.000007: authorities, sponsor's monitors and auditors) with direct access should take all rea sonable
p.000007: precautions within the constraints of the applicable regulatory requirement(s) to maintain the
p.000007: confidentiality of subjects' identities and sponsor’s proprietary information.
p.000007:
p.000007: 1.22 Documentation
p.000007: All records, in any form (inclu ding, but not limited to, written, electronic, magnetic, a nd
p.000007: optical records, and scans, x-rays, and electrocardiograms) that describe or record the
p.000007: methods, conduct, and/or results of a trial, the factors affecting a trial, and the action s
p.000007: taken.
p.000007:
p.000007: 1.23 Ess en tial Documents
p.000007: Documents which in divid ually and collectively permit evaluation of the conduct of a study and the
p.000007: quality of the data produced (see 8. Essential Documents for the Conduct of a Clinical T r i a l ) .
p.000007:
p.000007: 1.24 Good Clinical Practice (GCP)
p.000007: A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting
p.000007: of clinical trials that provides assurance that the data and reported results are
p.000007: credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are
p.000007: protected.
p.000007:
p.000007: 1.25 Independent Data-Monitoring Committee (IDMC) ( Data and Safety Monitoring Board, Monitoring Committee,
p.000007: Data
p.000007: Monitoring Committee)
p.000007: An independent data-monitoring committee that may be established by the sponsor to assess at intervals
...
p.000048: applicable labelling regulations and appropriateness of
p.000048: instructions provided to the subjects
p.000048: Investigator/ I ns tit u tio n
p.000048: Sponso r
p.000048:
p.000048:
p.000048: X
p.000048:
p.000048: 8.2.14 INSTRUCTIONS FOR HANDLING OF
p.000048: INVESTIGATIONAL
p.000048: P RODUCT( S) AND TRIAL- RELATED MATERIALS
p.000048: (if not included in protocol or Investigator’s Brochure)
p.000048: 8.2.15 SHIPPING RECORDS FOR INVESTIGATIONAL
p.000048: P RODUCT( S) AND TRIAL- RELATED MATERIALS
p.000048:
p.000048:
p.000048:
p.000048: 8.2.16 CERTIFICATE( S) OF ANALYSIS OF INVESTIGATIONAL
p.000048: P RODUCT( S) SHI PP ED
p.000048: 8.2.17 DECODING P ROCEDURES FOR BLINDED TRIALS
p.000048: To document instructions needed to ensure proper storage,
p.000048: packaging, dispensing and
p.000048: disposition of investigational products and trial-related
p.000048: mat e r i a ls
p.000048:
p.000048:
p.000048: To document shipment dates, batch numbers and method of shipment of investigational product(s) and
p.000048: trial-related
p.000048: materials. Allows tracking of
p.000048: product batch, review of shipping conditions, and accountability
p.000048: To document identity, purity, and strength of investigational
p.000048: product(s) to be used in the trial
p.000048: To document how, in case of an emergency, identity of blinded investigational product can be
p.000048: revealed without breaking the
p.000048: blind for the remaining subjects' treatment
p.000048: X X
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: X X
p.000048: (third party if applicable)
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: X
p.000048:
p.000048: 8.2.18 Master Ra ndom isatio n List To document method for
p.000048: randomisation of trial population
p.000048: X
p.000048: (third party if applicable)
p.000048:
p.000048:
p.000048: 8.2.19 P r e-Trial Monitori ng R epo rt To document that the site is
p.000048: X
p.000048: suitable for the trial (may be combined with 8.2.20)
p.000048:
p.000048: 8.2.20 Trial In itiatio n Monitori ng R epo rt
p.000048: To document that trial procedures X X were reviewed with the
p.000048: investigator and the
p.000048: investigator’s trial staff ( may be combined with 8.2.19)
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000049: 49
p.000049:
p.000049: ■ 3CC1a _____________________________________________________________
p.000049:
p.000049:
p.000049:
p.000049: 8.3 During the Clinical Conduct of the Trial
p.000049: In addition to having on file the above documents, the following should be added to the file s during
p.000049: the trial as evidence that all new relevant information is documented as it becomes availa ble
p.000049:
p.000049:
p.000049: Titl e of Document Pu rpose
p.000049: Located i n Files of
p.000049:
p.000049: Investigator/ I ns tit u tio n
p.000049: Sponso r
p.000049:
p.000049: 8.3.1 INVESTIGATOR’S BROCHURE U P DATES
p.000049:
p.000049:
p.000049: 8.3.2 ANY REVISION TO:
p.000049: – protocol/amendment(s) and CRF
p.000049: – informed consent form
p.000049: – any other written information provided to subjects
p.000049: – advertisement for subject recruitment (if used)
p.000049: 8.3.3 DATED, DOCUMENTED
p.000049: A PP ROVAL/ FAVOURAB LE
...
Political / vulnerable
Searching for indicator vulnerable:
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p.000011: ke
p.000011: important trial-related decisions (e.g., associates, residents, research fellows). See a l so
p.000011: Investigator.
p.000011:
p.000011: 1.57 Subject/Trial Subject
p.000011: An individual who participates in a clinical trial, either as a recipient of the inves tigational
p.000011: product(s) or as a control.
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000012: 12
p.000012:
p.000012: _____________________________________________________________ 3CC1a ■
p.000012:
p.000012:
p.000012:
p.000012: 1.58 Subject Identification Code
p.000012: A unique identifier assigned by the investigator to each trial subject to protect the s ubject's
p.000012: identity and used in lieu of the subject's name when the investigator reports adverse events and/or
p.000012: other trial related data.
p.000012:
p.000012: 1.59 Trial Site
p.000012: The location(s) where trial-related activities are actually conducted.
p.000012:
p.000012:
p.000012: 1.60 Unexpected Adverse Drug Reaction
p.000012: An adverse reaction, the nature or severity of which is not consistent with the applicable
p.000012: product information (e.g., Investigator's Brochure for an unapproved investigational product or package
p.000012: insert/summary of product characteristics for an a pproved product) (see note for guidance on Clinical
p.000012: Safety Data Management: Definitions and Standards for Expedited Reporting ).
p.000012:
p.000012: 1.61 Vulnerable Subjec ts
p.000012: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
p.000012: expectation, whether justified or not, of benefits associated with participation, or of a
p.000012: retaliatory response from senior members of a hierarchy in case of refusal to participate.
p.000012: Examples are members of a group with a hierarchical structure, such as medical, p harmacy, dental, and
p.000012: nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
p.000012: industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
p.000012: include patients with in curable diseases, persons in nur s i n g homes, unemployed or
p.000012: impoverished persons, patients in emergency situations, ethnic minority groups, homeless
p.000012: persons, nomads, refugees, minors, and those incapable of giving consent.
p.000012:
p.000012: 1.62 Well-being ( of the trial subjects)
p.000012: The physical and mental integrity of the subjects participating in a clinical trial.
p.000012:
p.000012:
p.000012:
p.000012: 2. THE PRINCIPLES OF ICH GCP
p.000012: 2.1 Clinical trials should be conducted in accordance with the ethical principles that
p.000012: have their origin in the Declaration of Helsinki, and that are consistent with GCP and the
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
p.000012: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000012: considerations and should prevail over interests of science and society.
...
p.000013: 2.8 Each individual involved in conducting a trial should be qualified by education,
p.000013: training, and experience to perform his or her respective task(s).
p.000013: 2.9 Freely given informed consent should be obtained from every subject prior to clinical trial
p.000013: participation.
p.000013: 2.10 All clinical trial information should be recorded, handled, and stored in a way that
p.000013: allows its accurate reporting, interpretation and verification.
p.000013: 2.11 The confidentiality of records that could identify subjects should be protected,
p.000013: respecting the privacy and confidentiality rules in accordance with the applicable regulatory
p.000013: requirement(s).
p.000013: 2.12 Investigational products should be manufactured, handled, and stored in accor d ance with
p.000013: applicable good manufacturing practice (GMP). They should be used in accordance with the approved
p.000013: protocol.
p.000013: 2.13 Systems with procedures that assure the quality of every aspect of the trial should be im
p.000013: plemented.
p.000013:
p.000013:
p.000013: 3. INSTITUTIONAL REVIEW BOARD/INDE P ENDENT ETHICS COMMITTEE (IRB/IEC)
p.000013: 3.1 R espons ibiliti es
p.000013: 3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special
p.000013: attention should be paid to trials that may include vulnerable subjects.
p.000013: 3.1.2 The IRB/IEC should obtain the following documents:
p.000013: trial protocol(s)/amendment(s), written informed consent form(s) and consent fo rm updates that
p.000013: the investigator proposes for use in the trial, subject rec ruitment procedures (e.g.
p.000013: advertisements), written information to be provided to subjects, Investigator's Brochure (IB),
p.000013: available safety information, information about payments and compensation available
p.000013: to subjects, the investigator’s current curriculum vitae and/or other documentation evidencing
p.000013: qualifications, and any other documents that the IRB/IEC may need to fulfil its responsibilities.
p.000013: The IRB/IEC should review a proposed clinical trial within a reasonable time a nd document its
p.000013: views in writing, clearly identifying the trial, the documents reviewed and the dates for the
p.000013: following:
p.000013: • approval/favourable opinion;
p.000013: • modifications required prior to i t s approval/favourable opinion;
p.000013:
p.000013:
p.000014: 14
p.000014:
p.000014: _____________________________________________________________ 3CC1a ■
p.000014:
p.000014:
p.000014:
p.000014: • disapproval/negative opinion; and
p.000014: • termination/suspension of any prior approval/favourable opinion.
...
Health / Cognitive Impairment
Searching for indicator impaired:
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p.000040: – Reproductive toxicity
p.000040: – Genotoxicity (mutagenicity)
p.000040:
p.000040: 7.3.6 Effects in Hu ma ns
p.000040: Introduction:
p.000040: A thorough discussion of the known effects of the investigational product(s) in human s should
p.000040: be provided, including information on pharmacokinetics, metabolis m,
p.000040: pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where
p.000040: possible, a summary of each completed clinical trial should be provided. I nformation should also be
p.000040: provided regarding results of any use of the investigational product(s) other than from in clinical
p.000040: trials, such as from experience during marketing.
p.000040:
p.000040:
p.000041: 41
p.000041:
p.000041: ■ 3CC1a _____________________________________________________________
p.000041:
p.000041:
p.000041:
p.000041: a) Pharmacokinetics and Product Metabolism in Humans
p.000041: – A summary of information on the pharmacokinetics of the inves tigational product(s)
p.000041: should be presented, including the following, if available:
p.000041: – Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma
p.000041: protein binding, distribution, and elimination).
p.000041: – Bioavailability of the investigational product (absolute, where possible, and/or relative)
p.000041: using a reference dosage form.
p.000041: – Population subgroups (e.g., gender, age, and impaired organ function).
p.000041: – Interactions (e.g., product-product interactions and effects of food).
p.000041: – Other pharmacokinetic data (e.g., results of population studies performed within clinical
p.000041: trial(s).
p.000041: b) Safety and Efficacy
p.000041: A summary of information should be provided about the inves tigational
p.000041: product’s/products’ (inclu ding metabolites, where appropriate) safety, pharmaco- dynamics,
p.000041: efficacy, and dose response that were obtained from preceding trials i n humans (healthy
p.000041: volunteers and/or patients). The implications of this i nformat ion should be discussed. In cases
p.000041: where a number of clinical trials have been completed, the use of summaries of safety and
p.000041: efficacy across multiple trials by indications i n subgroups may provide a clear presentation of the
p.000041: data. Tabular summaries of a dver se drug reactions for all the clinical trials (inclu
p.000041: ding those for all the studied indications) would be useful. Important differences
p.000041: in adverse drug reaction patterns/incidences across indications or subgroups should be discussed.
p.000041: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated
p.000041: on the basis of prior experiences with the product under inves tigation and with related
...
Health / Drug Usage
Searching for indicator drug:
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p.000003:
p.000003:
p.000003:
p.000003: INTRODUCTION
p.000003: Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing,
p.000003: conducting, recording and reporting trials that involve the participation of human subjects.
p.000003: Compliance with this standard provides public assurance that the rights, safety and well-being of
p.000003: trial subjects are protected, consistent with the principles that have their origin in the Declaration
p.000003: of Helsinki, and that the clinical trial data are credible.
p.000003: The objective of this ICH GCP Guideline is to pr ovide a unified standard for the European Union
p.000003: (EU), J apan and the United States to facilitate the mutual acceptance of clinical data by the
p.000003: regulatory authorities in these jurisdictions.
p.000003: The guideline was developed with consideration of the current good clinical practices of the European
p.000003: Union, J apan, and the United States, as well as those of Australia, Canada, the Nordic countries
p.000003: and the World Health Organisation (WHO).
p.000003: This guideline should be followed when generating clinical trial data that are intended to be submitted
p.000003: to regulatory authorities.
p.000003: The principles established in this guideline may also be applied to other cli n
p.000003: ic a l investigations that may have an impact on the safety and well-being of human subjects.
p.000003:
p.000003:
p.000003: 1. GLOSSARY
p.000003: 1.1 Adverse Drug Reaction (ADR)
p.000003: In the pre-approval clinical experience with a new medicinal product or its new us ages,
p.000003: particularly as the therapeutic dose(s) may not be established: all noxious and uninten ded
p.000003: responses to a medicinal product related to any dose should be considered adverse d rug
p.000003: reactions. The phrase responses to a medicinal product means that a causal relationship between
p.000003: a medicinal product and an adverse event is at least a reasonable possibility, i.e. the
p.000003: relationship cannot be ruled out.
p.000003: Regarding marketed medicinal products: a response to a drug which is noxious a nd
p.000003: unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of
p.000003: diseases or for modif ication of physiological function (see note for guidance o n Clinical Safety
p.000003: Data Management: Definitions and Standards for Expedited Reporting ).
p.000003:
p.000003: 1.2 Adverse Event (AE)
p.000003: Any untoward medical occurrence in a patient or clinical investigation subject
p.000003: administered a pharmaceutical product and which does not necessarily have a cau s a l
p.000003: relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and
p.000003: unintended sign (inclu ding an abnormal laboratory fin ding), symptom, or dise a se temporally
p.000003: associated with the use of a medicinal (investigational) product, whether or not related to the
p.000003: medicinal (investigational) product (see note for guidance on Clinical S afety Data Management:
p.000003: Definitions and Standards for Expedited Reporting ).
p.000003:
p.000005: 5
p.000005:
p.000005: ■ 3CC1a _____________________________________________________________
p.000005:
p.000005:
p.000005:
p.000005: 1.3 Amendmen t ( to t he protocol)
p.000005: See Protocol Amendment.
p.000005:
p.000005:
p.000005: 1.4 Applicabl e R egulatory R e q u ir emen t( s)
p.000005: Any law(s) and regulation(s) addressing the conduct of clinical trials of inves tigational
p.000005: products.
p.000005:
p.000005: 1.5 Approval (in relation to Institutional Revie w Boards)
p.000005: The affirmative decision of the IRB that the clinical trial has been reviewed and may be
...
p.000010: these could be provided in other protocol referenced documents. Throughout the GCP Guideline the term
p.000010: protocol refers to protocol and protocol amendments.
p.000010:
p.000010: 1.45 P rotocol Amendmen t
p.000010: A written description of a change(s) to or formal clarification of a protocol.
p.000010:
p.000010:
p.000010: 1.46 Quality Assurance (QA)
p.000010: All those planned and systematic actions that are established to ensure that the trial i s
p.000010: performed and the data are generated, documented (recorded), and reported in com pli ance with Good
p.000010: Clinical Practice (GCP) and the applicable regulatory requirement(s).
p.000010:
p.000010: 1.47 Quality Control (QC)
p.000010: The operational techniques and activities undertaken within the quality assurance system to verify that
p.000010: the requirements for quality of the trial-related activities have been fulfilled.
p.000010:
p.000010: 1.48 Ra ndom isatio n
p.000010: The process of a ssigning trial subjects to treatment or control groups using an element of chance
p.000010: to determine the assignments in order to reduce bias.
p.000010:
p.000010: 1.49 R egulatory Au t horities
p.000010: Bodies having the power to regulate. In this GCP guideline the expression Regulatory
p.000010: Authorities includes the authorities that review submitted clinical data and those that
p.000010: conduct inspections (see 1.29). These bodies are sometimes referred to as competent
p.000010: authorities.
p.000010:
p.000010: 1.50 Serious Adverse Event ( SAE) or Serious Adverse Drug Reaction ( Serious ADR)
p.000010: Any untoward medical occurrence that at any dose:
p.000010: • results in death,
p.000010: • is life-threatening,
p.000010: • requires inpatient hospitalisation or prolongation of existing hospitalisation,
p.000010: • results in persistent or significant disability/incapacity, or
p.000010: • is a congenital anomaly/birth defect
p.000010: (see the note for guidance on Clinical Safety Data Management: Definitions and Standards fo r Expedited
p.000010: Reporting ).
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: ■ 3CC1a _____________________________________________________________
p.000011:
p.000011:
p.000011:
p.000011: 1.51 Source Data
p.000011: All information in original records and certified copies of original records of cli n ic a l
p.000011: findings, observations, or other activities in a clinical trial necessary for the reconstruction and
p.000011: evaluation of the trial. Source data are contained in source documents (original recor ds or certified
p.000011: copies).
p.000011:
p.000011: 1.52 Source Documents
p.000011: Original documents, data, and records (e.g., hospital records, clinical and office charts,
p.000011: laboratory notes, memoranda, subjects' diaries or evaluation checklists, p harmacy
p.000011: dispensing records, recorded data from automated instruments, copies or transcriptions certified
p.000011: after verification as being accurate copies, microfiches, photographic negatives, microfilm or
...
p.000011: of a sponsor and those of an investigator.
p.000011:
p.000011: 1.55 Standard Operating Procedures ( SOP s)
p.000011: Detailed, written instructions to achieve uniformity of the performance of a specific
p.000011: function.
p.000011:
p.000011: 1.56 Subinvestigator
p.000011: Any individual member of the clinical trial team designated and supervised by the
p.000011: investigator at a trial site to perform critical trial-related procedures a nd/or to m a
p.000011: ke
p.000011: important trial-related decisions (e.g., associates, residents, research fellows). See a l so
p.000011: Investigator.
p.000011:
p.000011: 1.57 Subject/Trial Subject
p.000011: An individual who participates in a clinical trial, either as a recipient of the inves tigational
p.000011: product(s) or as a control.
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000012: 12
p.000012:
p.000012: _____________________________________________________________ 3CC1a ■
p.000012:
p.000012:
p.000012:
p.000012: 1.58 Subject Identification Code
p.000012: A unique identifier assigned by the investigator to each trial subject to protect the s ubject's
p.000012: identity and used in lieu of the subject's name when the investigator reports adverse events and/or
p.000012: other trial related data.
p.000012:
p.000012: 1.59 Trial Site
p.000012: The location(s) where trial-related activities are actually conducted.
p.000012:
p.000012:
p.000012: 1.60 Unexpected Adverse Drug Reaction
p.000012: An adverse reaction, the nature or severity of which is not consistent with the applicable
p.000012: product information (e.g., Investigator's Brochure for an unapproved investigational product or package
p.000012: insert/summary of product characteristics for an a pproved product) (see note for guidance on Clinical
p.000012: Safety Data Management: Definitions and Standards for Expedited Reporting ).
p.000012:
p.000012: 1.61 Vulnerable Subjec ts
p.000012: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
p.000012: expectation, whether justified or not, of benefits associated with participation, or of a
p.000012: retaliatory response from senior members of a hierarchy in case of refusal to participate.
p.000012: Examples are members of a group with a hierarchical structure, such as medical, p harmacy, dental, and
p.000012: nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
p.000012: industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
p.000012: include patients with in curable diseases, persons in nur s i n g homes, unemployed or
...
p.000015: 3.3.4 De termining the frequency of continuing review, as appropriate.
p.000015: 3.3.5 Providing, according to the applicable regulatory requirements, expedited review and
p.000015: approval/favourable opinion of minor change(s) in ongoing trials that have the
p.000015: approval/favourable opinion of the IRB/IEC.
p.000015: 3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its
p.000015: written approval/favourable opinion of the trial.
p.000015: 3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated
p.000015: without prior written IRB/IEC approval/favourable opinion of an appropriate am e n d m e nt, except
p.000015: when necessary to eliminate immediate hazards to the subjects or when the chan ge( s) involves only
p.000015: logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s))
p.000015: (see 4.5.2).
p.000015: 3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
p.000015: a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial
p.000015: subjects (see 3.3.7, 4.5.2, 4.5.4).
p.000015: b) Changes increasing the r isk to subjects and/or affecting significantly the conduct
p.000015: of the trial (see 4.10.2).
p.000015: c ) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000015: d) New information that may affect adversely the safety of the subjects or the
p.000015: conduct of the trial.
p.000015: 3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution conce rn
p.000015: i n g:
p.000015: a) I t s trial-related decisions/opinions.
p.000015: b) The reasons for i t s decisions/opinions.
p.000015: c ) Procedures for appeal of i t s decisions/opinions.
p.000015:
p.000015:
p.000015:
p.000016: 16
p.000016:
p.000016: _____________________________________________________________ 3CC1a ■
p.000016:
p.000016:
p.000016:
p.000016: 3.4 R eco rds
p.000016: The IRB/IEC should retain all relevant records (e.g., written procedures, membership li s t s, lis t s
p.000016: of occupations/affiliations of members, submitted documents, minutes of meetings, a nd correspondence) for
p.000016: a period of at least 3 years after completion of the trial and make them available upon request
p.000016: from the regulatory authority(ies).
p.000016: The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written
p.000016: procedures and membership lis t s.
p.000016:
p.000016:
p.000016: 4. INVESTIGATOR
p.000016: 4.1 Inves tigator’s Qualifications and Agreemen ts
p.000016: 4.1.1 The investigator(s) should be qualified by education, training, and experience to
p.000016: assume responsibility for the proper conduct of the trial, should meet all the q ualification s
...
p.000022: investigator/institution should make available for direct access all requ ested trial-related recor
p.000022: ds.
p.000022:
p.000022: 4.10 Progress Reports
p.000022: 4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC
p.000022: annually, or more frequently, if requested by the IRB/IEC.
p.000022: 4.10.2 The investigator should promptly provide written rep orts to the sponsor, the IRB/IEC (see
p.000022: 3.3.8) and, where applicable, the institution on any changes significantly affecting the conduct of
p.000022: the trial, and/or increasing the risk to subjects.
p.000022:
p.000022: 4.11 Safety Reporting
p.000022: 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except
p.000022: for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies
p.000022: as not needing immediate reporting. The immediate reports should be followed promptly by
p.000022: detailed, written reports. The immediate and follow-up reports should ide ntify subjects by unique
p.000022: code numbers assigned to the trial subjects rather than by the subjects’ names, personal
p.000022: identification numbers, and/or addresses. The investigator should a l so comply with the applicable
p.000022: regulatory requirement(s) rel ated to the reporting of unexpected serious adverse drug reactions to
p.000022: the regulatory authority(ies) and the IRB/IEC.
p.000022: 4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as cr i t ica l to
p.000022: safety evaluations should be reported to the sponsor according to the reporting
p.000022: requirements and within the time periods specified by the sponsor in the protocol.
p.000022: 4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any
p.000022: additional requested information (e.g., autopsy reports and terminal medical reports).
p.000022:
p.000022:
p.000022:
p.000022:
p.000023: 23
p.000023:
p.000023: ■ 3CC1a _____________________________________________________________
p.000023:
p.000023:
p.000023:
p.000023: 4.12 Premature Termination or Suspension of a Trial
p.000023: If the trial is prematurely terminated or suspended for any reason,
p.000023: the
p.000023: investigator/institution should promptly inform the trial subjects, should assure appropr iate therapy
p.000023: and follow-up for the s ubjects, and, where required by the applicable regulatory requirement(s),
p.000023: should inform the regulatory authority(ies). In addition:
p.000023: 4.12.1 If the investigator terminates or suspends a trial without prior agreement of the
p.000023: sponsor, the investigator should inform the institution where applicable, and the
...
p.000028: regulatory requirement(s), whichever represents the longer retention period.
p.000028:
p.000028: 5.15 R ecord Access
p.000028: 5.15.1 The sponsor should ensure that it is specified in the protocol or other written
p.000028: agreement that the investigator(s)/institution(s) provide direct access to
p.000028: source
p.000028:
p.000028:
p.000029: 29
p.000029:
p.000029: ■ 3CC1a _____________________________________________________________
p.000029:
p.000029:
p.000029:
p.000029: data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory
p.000029: inspection.
p.000029: 5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to
p.000029: his/her original medical records for trial-related monitoring, audit, IRB/IEC review, a nd regulatory
p.000029: inspection.
p.000029:
p.000029: 5.16 Safe ty Informa tio n
p.000029: 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the inves tigational
p.000029: product(s).
p.000029: 5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) a nd the
p.000029: regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact
p.000029: the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial.
p.000029:
p.000029: 5.17 Adverse Drug Reaction Reporting
p.000029: 5.17.1 The sponsor should expedite the reporting to all
p.000029: conce rn ed investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the
p.000029: regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected.
p.000029: 5.17.2 Such expedited reports should co mply with the applicable regulatory requir ement(s) and with
p.000029: the note for guidance on Clinical Safety Data Management: Definitions and Standards for
p.000029: Expedited Reporting .
p.000029: 5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates a nd
p.000029: periodic reports, as required by applicable regulatory requirement(s).
p.000029:
p.000029: 5.18 Monito ri ng
p.000029: 5.18.1 Purpose
p.000029: The purposes of trial monitoring are to verify that:
p.000029: a) The rights and well-being of human subjects are protected.
p.000029: b) The reported trial data are accurate, complete, and verifiable from source documents.
p.000029: c ) The conduct of the trial is in compliance with the currently
p.000029: approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
p.000029:
p.000029: 5.18.2 Selection a n d Qualifica tions of Monitors
p.000029: a) Monitors should be appointed by the sponsor.
p.000029: b) Monitors should be appropriately trained, and should have the scientific and/or
p.000029: clinical knowledge needed to monitor the trial adequately. A monitor’s q ualification s should be
p.000029: documented.
p.000029: c ) Monitors should be thoroughly familiar with the investigational product(s), the
p.000029: protocol, written informed consent form and any other written information to be provided
...
p.000041: should be presented, including the following, if available:
p.000041: – Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma
p.000041: protein binding, distribution, and elimination).
p.000041: – Bioavailability of the investigational product (absolute, where possible, and/or relative)
p.000041: using a reference dosage form.
p.000041: – Population subgroups (e.g., gender, age, and impaired organ function).
p.000041: – Interactions (e.g., product-product interactions and effects of food).
p.000041: – Other pharmacokinetic data (e.g., results of population studies performed within clinical
p.000041: trial(s).
p.000041: b) Safety and Efficacy
p.000041: A summary of information should be provided about the inves tigational
p.000041: product’s/products’ (inclu ding metabolites, where appropriate) safety, pharmaco- dynamics,
p.000041: efficacy, and dose response that were obtained from preceding trials i n humans (healthy
p.000041: volunteers and/or patients). The implications of this i nformat ion should be discussed. In cases
p.000041: where a number of clinical trials have been completed, the use of summaries of safety and
p.000041: efficacy across multiple trials by indications i n subgroups may provide a clear presentation of the
p.000041: data. Tabular summaries of a dver se drug reactions for all the clinical trials (inclu
p.000041: ding those for all the studied indications) would be useful. Important differences
p.000041: in adverse drug reaction patterns/incidences across indications or subgroups should be discussed.
p.000041: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated
p.000041: on the basis of prior experiences with the product under inves tigation and with related
p.000041: products. A description should also be provided of the precautions or special monitoring to be done
p.000041: as part of the investigational use of the product(s).
p.000041: c ) Marketing Experience
p.000041: The IB should identify countries where the investigational product has been mark e ted or approved. Any
p.000041: significant information arising from the marketed use should be summarised (e.g.,
p.000041: formulations, dosages, routes of administration, and a dver se product reactions). The IB
p.000041: should also identify all the countries where the investigational product did not
p.000041: receive approval/registration for marketing or was withdrawn from marketing/registration.
p.000041:
p.000041: 7.3.7 Su mma ry of Da t a a n d Gui da nce for the Investig a tor
p.000041: This section should provide an overall discussion of the nonclinical and clinical data, a nd should
p.000041: summarise the information from various sources on different aspects of the
p.000041: investigational product(s), wherever possible. In this way, the investigator can be provided with the
p.000041: most informative interpretation of the available data and with an assessment of the implications of
p.000041: the information for future clinical trials.
p.000041: Where appropriate, the published reports on related products should be discussed. This could help the
p.000041: investigator to anticipate adverse drug reactions or other problems in clinical trials.
p.000041: The overall aim of this section is to provide the i nves tigator w it h a
p.000041: clear understanding of the possible risks and adverse reactions, and of the specific tests,
p.000041:
p.000042: 42
p.000042:
p.000042: _____________________________________________________________ 3CC1a ■
p.000042:
p.000042:
p.000042:
p.000042: observations, and precautions that may be needed for a c li n ical trial. T h is
p.000042: understanding should be based on the available physical, chemica l ,
p.000042: pharmaceutical, pharmacological, toxicological, and c li n ical i nfo r ma tio n on the
p.000042: i nves tigatio nal product( s). Guidance should also be provided to the c l i n ical
p.000042: investigator on the r ecogn itio n and treatment of possibl e overdose and adverse drug
p.000042: reactions that is based on prev io us human experience and on the
p.000042: pharmacology of t he i nves tigatio nal product.
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000043: 43
p.000043:
p.000043: ■ 3CC1a _____________________________________________________________
p.000043:
p.000043:
p.000043:
p.000043: 7.4 APP ENDIX 1
p.000043:
p.000043: TITLE PAGE (Example)
p.000043:
p.000043: S P ONSOR'S NAME
p.000043:
p.000043: P roduct:
p.000043:
p.000043: R esearch Number:
p.000043:
p.000043: Name ( s ): Chemical, Generic (if approved)
p.000043: Trade Name(s) (if legally permissible and desired by the sponsor)
p.000043:
p.000043:
p.000043:
p.000043:
p.000043: INVESTIGATOR’S BROCHURE
p.000043:
p.000043: Edition Number:
p.000043: Release Date:
p.000043:
p.000043:
p.000043:
p.000043: Replaces Previous Edition Number: Date:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000044: 44
p.000044:
...
p.000050: trial, to medical treatment, and
p.000050: history of subject
p.000050:
p.000050: 8.3.14 SIGNED, DATED AND
p.000050: COMPLETED CASE RE PORT FORMS (CRF)
p.000050: To document that the investigator or authorised member of the
p.000050: investigator’s staff confirms the observations recorded
p.000050: X
p.000050: (copy)
p.000050: X
p.000050: (or igi na l)
p.000050:
p.000050:
p.000050:
p.000050:
p.000051: 51
p.000051:
p.000051: ■ 3CC1a _____________________________________________________________
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: Titl e of Document Pu rpose
p.000051: Located i n Files of
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: 8.3.15 DOCUMENTATION OF CRF CORRECTIONS
p.000051:
p.000051:
p.000051:
p.000051: To document all changes/
p.000051: additions or corrections made to CRF after initial data were
p.000051: recorded
p.000051: Investigator/ I ns tit u tio n
p.000051: X
p.000051: (copy)
p.000051: Sponso r
p.000051:
p.000051:
p.000051: X
p.000051: (or igi na l)
p.000051:
p.000051: 8.3.16 NOTIFICATION BY
p.000051: ORIGINATING INVESTIGATOR TO S PONSOR OF SERIOUS
p.000051: ADVERSE EVENTS AND RELATED REPORTS
p.000051: Notification by originating X X investigator to
p.000051: sponsor of serious
p.000051: adverse events and related reports in accordance with 4.11
p.000051:
p.000051: 8.3.17 NOTIFICATION BY S PONSOR AND/OR INVESTIGATOR,
p.000051: WHERE APPLICABLE, TO REGULATORY
p.000051: AUTHORITY(IES) AND
p.000051: IRB( S)/IEC( S) OF UNEXP ECTED SERIOUS ADVERSE DRUG
p.000051: REACTIONS AND OF OTHER SAFETY INFORMATION
p.000051: Notification by sponsor and/or
p.000051: investigator, where applicable, to regulatory authorities and
p.000051: IRB(s)/IEC(s) of unexpected
p.000051: serious adverse drug reactions in accordance with 5.17 and 4.11.1
p.000051: and of other safety information in accordance with 5.16.2
p.000051: X X
p.000051: (where required)
p.000051:
p.000051: 8.3.18 NOTIFICATION BY S PONSOR TO INVESTIGATORS OF SAFETY
p.000051: INFORMATION
p.000051:
p.000051:
p.000051: 8.3.19 INTERIM OR ANNUAL
p.000051: RE PORTS TO IRB/IEC AND AU THORITY(IES)
p.000051: Notification by sponsor to investigators of safety
p.000051: information in accordance with 5.16.2
p.000051: Interim or annual reports provided to IRB/IEC in
p.000051: accordance with 4.10 and to
p.000051: authority(ies) in accordance with 5.17.3
p.000051: X X
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: X X
p.000051: (where required)
p.000051:
p.000051: 8.3.20 SUB JECT SCREENING LOG To document identification of
p.000051: subjects who entered pre-trial scr ee n i n g
p.000051: X X
p.000051: (where required)
p.000051:
p.000051: 8.3.21 SUB J ECT IDENTIFICATION CODE LIST
p.000051: To document that X
p.000051: investigator/institution keeps a confidential lis t of names of all
p.000051: subjects allocated to trial numbers on enrolling in the trial. Allows
p.000051: investigator/institution to reveal identity of any subject
p.000051: 8.3.22 SUB J ECT ENROLMENT LOG To document chronological X
p.000051: enrolment of subjects by trial number
p.000051:
p.000051: 8.3.23 INVESTIGATIONAL P RODUCTS ACCOUNTABILITY AT THE SITE
...
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p.000014: appropriate to the degree of risk to human subjects, but at least once per year.
p.000014: 3.1.5 The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given
p.000014: to subjects when, in the judgement of the IRB/IEC, the additional information would add meaningfully
p.000014: to the protection of the rights, safety and/or well-being of the subjects.
p.000014: 3.1.6 When a non-therapeutic trial is to be carried out with the consent of the subject’s
p.000014: legally acceptable representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed
p.000014: protocol and /or other document(s) adequately addresses relevant ethical conce rn s and meets
p.000014: applicable regulatory requirements for such trials.
p.000014: 3.1.7 Where the protocol indicates that prior consent of the trial subject or the subject’s
p.000014: legally acceptable representative is not possible (see 4. 8.15), the IRB/IEC should de t ermine that
p.000014: the proposed protocol and /or other document(s) adequately addresses relevant ethical concerns and
p.000014: meets applicable regulatory requirements for such trials (i.e. in e m e r ge ncy situations).
p.000014: 3.1.8 The IRB/IEC should review both the amount and method of payment to subjects to assure
p.000014: that neither presents problems of coercion or undue influence on the trial subjects. Payments to
p.000014: a subject should be prorated and not wholly contingent on completion of the tr i a l by the subject.
p.000014: 3.1.9 The IRB/IEC should ensure that information regarding payment to subjects,
p.000014: including the methods, amounts, and schedule of payment to trial subjects, is set forth in the
p.000014: written informed consent form and any other written information to be provided to subjects. The way
p.000014: payment will be prorated should be specified.
p.000014:
p.000014: 3.2 Composition, Functions and Operations
p.000014: 3.2.1 The IRB/IEC should consist of a reasonable number of members, who collectively have the
p.000014: qualifications and experience to review and evaluate the science, medical aspects, and ethics of the
p.000014: proposed trial. I t is recommended that the IRB/IEC should include:
p.000014: a) At least five members.
p.000014: b) At least one member whose primary area of interest is in a nonscientific area. c ) At
p.000014: least one member who is independent of the institution/trial site.
p.000014: Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial
p.000014: should vote/provide opinion on a trial-related matter.
p.000014: A lis t of IRB/IEC members and their qualifications should be maintained.
p.000014: 3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should
...
p.000018: have their origin in the Declaration of Helsinki. Prior to the beginning of the
p.000018: trial, the investigator should have the IRB/IEC's written approval/favourable opinion of the written
p.000018: informed consent form and any other written information to be provided to subjects.
p.000018:
p.000019: 19
p.000019:
p.000019: ■ 3CC1a _____________________________________________________________
p.000019:
p.000019:
p.000019:
p.000019: 4.8.2 The written informed consent form and any other written information to be provided to
p.000019: subjects should be revised whenever important new information becomes available that may be
p.000019: relevant to the subject’s consent. Any revised written informed consent form, a nd written
p.000019: information should receive the IRB/IEC's approval/favourable opinion in advance of use. The subject or the
p.000019: subject’s legally acceptable representative should be informed in a t imely manner if new
p.000019: information becomes available that may be relevant to the subject’s willingness to continue
p.000019: participation in the trial. The communication of this i nformat ion should be documented.
p.000019: 4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a
p.000019: subject to participate or to continue to participate in a trial.
p.000019: 4.8.4 None of the oral and written information concerning the trial, including the written informed
p.000019: consent form, should contain any language that causes the subject or the subject’s legally
p.000019: acceptable representative to waive or to appear to waive any legal rights, or that releases
p.000019: or appears to release the investigator, the institution, the sponsor, or their agents from
p.000019: liability or negligence.
p.000019: 4.8.5 The investigator, or a person designated by the investigator, should fully inform the
p.000019: subject or, if the subject is unable to provide informed consent, the subject’s leg a
p.000019: lly acceptable representative, of all pertinent aspects of the trial including the
p.000019: written information and the approval/favourable opinion by the IRB/IEC.
p.000019: 4.8.6 The language u sed in the oral and written information about the trial, including the
p.000019: written informed consent form, should be as non-technical as practical and should be
p.000019: understandable to the subject or the subject's legally acceptable representative and the
p.000019: impartial witness, where applicable.
...
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p.000038: appropriate:
p.000038:
p.000038: 7.3.1 T a ble of Contents
p.000038: An example of the Table of Contents is given in Appendix 2.
p.000038:
p.000038: 7.3.2 Su mma ry
p.000038: A brief s ummary (preferably not exceeding two pages) should be given, highlighting the
p.000038: significant physical, chemical, pharmaceutical, pharmacological, toxicological,
p.000038: pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of
p.000038: clinical development of the investigational product.
p.000038:
p.000038:
p.000038:
p.000039: 39
p.000039:
p.000039: ■ 3CC1a _____________________________________________________________
p.000039:
p.000039:
p.000039:
p.000039: 7.3.3 Introduction
p.000039: A brief introductory statement should be provided that contains the chemical name ( an d generic
p.000039: and trade name(s) when approved) of the investigational product(s), all active ingredients,
p.000039: the investigational product (s) pharmacological class and its expected position within this class
p.000039: (e.g. advantages), the rationale for performing research with the investigational
p.000039: product(s), and the anticipated prophyla ctic, therapeutic, or diagnos t ic indication(s).
p.000039: Finally, the introductory statement should provide the general approach to be followed in evaluating
p.000039: the investigational product.
p.000039:
p.000039: 7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation
p.000039: A description should be provided of the investigational product substance(s) (inclu ding the chemical
p.000039: and/or structural formula(e)), and a brief summary should be given of the relevant
p.000039: physical, chemical, and pharmaceutical properties.
p.000039: To permit appropriate safety measures to be taken in the course of the trial, a description of the
p.000039: formulation(s) to be used, including excipients, should be provided and justified i f clinically
p.000039: relevant. Instructions for the storage and handling of the dosage form(s) should also be given.
p.000039: Any structural similarities to other known compounds should be mentioned.
p.000039:
p.000039: 7.3.5 Nonclinical Studies
p.000039: Introduction:
p.000039: The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, a nd
p.000039: investigational product metabolism studies should be provided in summ ary form. T h i s summary
p.000039: should address the methodology used, the results, and a discussion of the relevance
p.000039: of the findings to the investigated therapeutic and the possible unfavourable a nd unintended effects
p.000039: in humans.
p.000039: The information provided may include the following, as appropriate, if known/available:
p.000039: • Species tested
p.000039: • Number and sex of animals in each group
p.000039: • Unit dose (e.g., milligram/kilogram ( mg/kg))
p.000039: • Dose interval
p.000039: • Route of administration
p.000039: • Duration of dosing
p.000039: • Information on systemic distribution
p.000039: • Duration of post-exposure follow-up
p.000039: • Results, including the following aspects:
...
Health / Healthy People
Searching for indicator volunteers:
(return to top)
p.000040: trials, such as from experience during marketing.
p.000040:
p.000040:
p.000041: 41
p.000041:
p.000041: ■ 3CC1a _____________________________________________________________
p.000041:
p.000041:
p.000041:
p.000041: a) Pharmacokinetics and Product Metabolism in Humans
p.000041: – A summary of information on the pharmacokinetics of the inves tigational product(s)
p.000041: should be presented, including the following, if available:
p.000041: – Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma
p.000041: protein binding, distribution, and elimination).
p.000041: – Bioavailability of the investigational product (absolute, where possible, and/or relative)
p.000041: using a reference dosage form.
p.000041: – Population subgroups (e.g., gender, age, and impaired organ function).
p.000041: – Interactions (e.g., product-product interactions and effects of food).
p.000041: – Other pharmacokinetic data (e.g., results of population studies performed within clinical
p.000041: trial(s).
p.000041: b) Safety and Efficacy
p.000041: A summary of information should be provided about the inves tigational
p.000041: product’s/products’ (inclu ding metabolites, where appropriate) safety, pharmaco- dynamics,
p.000041: efficacy, and dose response that were obtained from preceding trials i n humans (healthy
p.000041: volunteers and/or patients). The implications of this i nformat ion should be discussed. In cases
p.000041: where a number of clinical trials have been completed, the use of summaries of safety and
p.000041: efficacy across multiple trials by indications i n subgroups may provide a clear presentation of the
p.000041: data. Tabular summaries of a dver se drug reactions for all the clinical trials (inclu
p.000041: ding those for all the studied indications) would be useful. Important differences
p.000041: in adverse drug reaction patterns/incidences across indications or subgroups should be discussed.
p.000041: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated
p.000041: on the basis of prior experiences with the product under inves tigation and with related
p.000041: products. A description should also be provided of the precautions or special monitoring to be done
p.000041: as part of the investigational use of the product(s).
p.000041: c ) Marketing Experience
p.000041: The IB should identify countries where the investigational product has been mark e ted or approved. Any
p.000041: significant information arising from the marketed use should be summarised (e.g.,
p.000041: formulations, dosages, routes of administration, and a dver se product reactions). The IB
p.000041: should also identify all the countries where the investigational product did not
...
Health / Mentally Disabled
Searching for indicator disability:
(return to top)
p.000010:
p.000010:
p.000010: 1.46 Quality Assurance (QA)
p.000010: All those planned and systematic actions that are established to ensure that the trial i s
p.000010: performed and the data are generated, documented (recorded), and reported in com pli ance with Good
p.000010: Clinical Practice (GCP) and the applicable regulatory requirement(s).
p.000010:
p.000010: 1.47 Quality Control (QC)
p.000010: The operational techniques and activities undertaken within the quality assurance system to verify that
p.000010: the requirements for quality of the trial-related activities have been fulfilled.
p.000010:
p.000010: 1.48 Ra ndom isatio n
p.000010: The process of a ssigning trial subjects to treatment or control groups using an element of chance
p.000010: to determine the assignments in order to reduce bias.
p.000010:
p.000010: 1.49 R egulatory Au t horities
p.000010: Bodies having the power to regulate. In this GCP guideline the expression Regulatory
p.000010: Authorities includes the authorities that review submitted clinical data and those that
p.000010: conduct inspections (see 1.29). These bodies are sometimes referred to as competent
p.000010: authorities.
p.000010:
p.000010: 1.50 Serious Adverse Event ( SAE) or Serious Adverse Drug Reaction ( Serious ADR)
p.000010: Any untoward medical occurrence that at any dose:
p.000010: • results in death,
p.000010: • is life-threatening,
p.000010: • requires inpatient hospitalisation or prolongation of existing hospitalisation,
p.000010: • results in persistent or significant disability/incapacity, or
p.000010: • is a congenital anomaly/birth defect
p.000010: (see the note for guidance on Clinical Safety Data Management: Definitions and Standards fo r Expedited
p.000010: Reporting ).
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: ■ 3CC1a _____________________________________________________________
p.000011:
p.000011:
p.000011:
p.000011: 1.51 Source Data
p.000011: All information in original records and certified copies of original records of cli n ic a l
p.000011: findings, observations, or other activities in a clinical trial necessary for the reconstruction and
p.000011: evaluation of the trial. Source data are contained in source documents (original recor ds or certified
p.000011: copies).
p.000011:
p.000011: 1.52 Source Documents
p.000011: Original documents, data, and records (e.g., hospital records, clinical and office charts,
p.000011: laboratory notes, memoranda, subjects' diaries or evaluation checklists, p harmacy
p.000011: dispensing records, recorded data from automated instruments, copies or transcriptions certified
p.000011: after verification as being accurate copies, microfiches, photographic negatives, microfilm or
p.000011: magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at
p.000011: medico-technical departments involved in the clinical trial).
p.000011:
p.000011: 1.53 Sponsor
p.000011: An individual, company, institution, or organisation which takes responsibility for the
p.000011: initiation, management, and/or financing of a clinical trial.
p.000011:
p.000011: 1.54 Sponsor-Inves tigator
...
Health / Mentally Incapacitated
Searching for indicator incapable:
(return to top)
p.000012: Safety Data Management: Definitions and Standards for Expedited Reporting ).
p.000012:
p.000012: 1.61 Vulnerable Subjec ts
p.000012: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
p.000012: expectation, whether justified or not, of benefits associated with participation, or of a
p.000012: retaliatory response from senior members of a hierarchy in case of refusal to participate.
p.000012: Examples are members of a group with a hierarchical structure, such as medical, p harmacy, dental, and
p.000012: nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
p.000012: industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
p.000012: include patients with in curable diseases, persons in nur s i n g homes, unemployed or
p.000012: impoverished persons, patients in emergency situations, ethnic minority groups, homeless
p.000012: persons, nomads, refugees, minors, and those incapable of giving consent.
p.000012:
p.000012: 1.62 Well-being ( of the trial subjects)
p.000012: The physical and mental integrity of the subjects participating in a clinical trial.
p.000012:
p.000012:
p.000012:
p.000012: 2. THE PRINCIPLES OF ICH GCP
p.000012: 2.1 Clinical trials should be conducted in accordance with the ethical principles that
p.000012: have their origin in the Declaration of Helsinki, and that are consistent with GCP and the
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
p.000012: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000012: considerations and should prevail over interests of science and society.
p.000012: 2.4 The available nonclinical and clinical information on an investigational product
p.000012: should be adequate to support the proposed clinical trial.
p.000012:
p.000012:
p.000013: 13
p.000013:
p.000013: ■ 3CC1a _____________________________________________________________
p.000013:
p.000013:
p.000013:
p.000013: 2.5 Clinical trials should be scientifically sound, and described in a clear,
p.000013: detailed protocol.
p.000013: 2.6 A trial should be conducted in compliance with the protocol that has received prior
...
Health / Physically Disabled
Searching for indicator illness:
(return to top)
p.000016: recruitment period.
p.000016: 4.2.2 The investigator should have sufficient time to properly conduct and complete the trial
p.000016: within the agreed trial period.
p.000016: 4.2.3 The investigator should have available an adequate number of qualified staff a nd
p.000016: adequate facilities for the foreseen duration of the trial to conduct the trial properly a nd
p.000016: s afely.
p.000016: 4.2.4 The investigator should ensure that all persons assisting with the trial
p.000016: are adequately informed about the protocol, the investigational product(s), and their trial-related duties
p.000016: and functions.
p.000016:
p.000016:
p.000016:
p.000016:
p.000016:
p.000016:
p.000017: 17
p.000017:
p.000017: ■ 3CC1a _____________________________________________________________
p.000017:
p.000017:
p.000017:
p.000017: 4.3 Medical Care of Trial Subjects
p.000017: 4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub-
p.000017: investigator for the trial, should be responsible for all trial-related medical (or de ntal)
p.000017: decision s .
p.000017: 4.3.2 During and following a subject’s participation in a trial, the investigator/institution should
p.000017: ensure that a dequate medical care is provided to a subject for any adverse events, inclu ding
p.000017: clinically significant laboratory values, related to the trial. The
p.000017: investigator/institution should inform a subject when medical care is needed for
p.000017: intercurrent illness(es) of which the investigator becomes aware.
p.000017: 4.3.3 It is recommended that the investigator inform the subject's primary physician about the
p.000017: subject's participation in the trial if the subject has a primary physician and if the
p.000017: subject agrees to the primary physician being informed.
p.000017: 4.3.4 Although a subject is not obliged to give his/her reason(s) for with d
p.000017: rawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the
p.000017: reason(s), while fully respecting the subject’s rights.
p.000017:
p.000017: 4.4 Communication w it h IRB/IEC
p.000017: 4.4.1 Before initiating a trial, the investigator/institution should have written and dated
p.000017: approval/favourable opinion from the IRB/IEC for the trial protocol, written i nform ed
p.000017: consent form, consent form updates, subject recruitment procedures (e.g., advertisements), and any
p.000017: other written information to be provided to subjects.
p.000017: 4.4.2 As part of the investigator’s/institution’s written application to the IRB/IEC, the
p.000017: investigator/institution should provide the IRB/IEC with a current copy of the I nves tigator' s Brochure.
p.000017: If the Investigator's Brochure is updated during the trial, the
p.000017: investigator/institution should supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
...
Health / Terminally Ill
Searching for indicator terminal:
(return to top)
p.000022: the trial, and/or increasing the risk to subjects.
p.000022:
p.000022: 4.11 Safety Reporting
p.000022: 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except
p.000022: for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies
p.000022: as not needing immediate reporting. The immediate reports should be followed promptly by
p.000022: detailed, written reports. The immediate and follow-up reports should ide ntify subjects by unique
p.000022: code numbers assigned to the trial subjects rather than by the subjects’ names, personal
p.000022: identification numbers, and/or addresses. The investigator should a l so comply with the applicable
p.000022: regulatory requirement(s) rel ated to the reporting of unexpected serious adverse drug reactions to
p.000022: the regulatory authority(ies) and the IRB/IEC.
p.000022: 4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as cr i t ica l to
p.000022: safety evaluations should be reported to the sponsor according to the reporting
p.000022: requirements and within the time periods specified by the sponsor in the protocol.
p.000022: 4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any
p.000022: additional requested information (e.g., autopsy reports and terminal medical reports).
p.000022:
p.000022:
p.000022:
p.000022:
p.000023: 23
p.000023:
p.000023: ■ 3CC1a _____________________________________________________________
p.000023:
p.000023:
p.000023:
p.000023: 4.12 Premature Termination or Suspension of a Trial
p.000023: If the trial is prematurely terminated or suspended for any reason,
p.000023: the
p.000023: investigator/institution should promptly inform the trial subjects, should assure appropr iate therapy
p.000023: and follow-up for the s ubjects, and, where required by the applicable regulatory requirement(s),
p.000023: should inform the regulatory authority(ies). In addition:
p.000023: 4.12.1 If the investigator terminates or suspends a trial without prior agreement of the
p.000023: sponsor, the investigator should inform the institution where applicable, and the
p.000023: investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the
p.000023: sponsor and the IRB/IEC a detailed written explanation of the termination or suspension.
p.000023: 4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should
p.000023: promptly inform the institution where applicable and the investigator/institution should promptly
p.000023: inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or
p.000023: suspension.
p.000023: 4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see
...
Social / Access to Social Goods
Searching for indicator access:
(return to top)
p.000006: a clinical trial.
p.000006:
p.000006: 1.15 Compliance ( in relation to trials)
p.000006: Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirement s, and the
p.000006: applicable regulatory requirements.
p.000006:
p.000006: 1.16 Confid en tiality
p.000006: Prevention of disclosure, to other than authorised individuals, of a sponsor's proprietary
p.000006: information or of a subject’s identity.
p.000006:
p.000006: 1.17 Contract
p.000006: A written, dated, and signed agreement between two or more involved parties that sets out any
p.000006: arrangements on delegation and distribution of tasks and obligations and, i f
p.000006: appropriate, on financial matters. The protocol may serve as the basis of a contract.
p.000006:
p.000006: 1.18 Co-ordinating Committee
p.000006: A committee that a sponsor may organise to co-ordinate the conduct of a multicentre trial.
p.000006:
p.000006:
p.000006: 1.19 Co-ordinating Investigator
p.000006: An investigator assigned the responsibility for the co-ordination of investigators at different centres
p.000006: participating in a multicentre trial.
p.000006:
p.000006: 1.20 Contract Research Organisation (CRO)
p.000006: A person or an organisation (commercial, academic, or other) contracted by the sponsor to perform
p.000006: one or more of a sponsor’s trial-related duties and functions.
p.000006:
p.000007: 7
p.000007:
p.000007: ■ 3CC1a _____________________________________________________________
p.000007:
p.000007:
p.000007:
p.000007: 1.21 Direct Access
p.000007: Permission to examine, analyse, verify, and reproduce any records and reports that are
p.000007: important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory
p.000007: authorities, sponsor's monitors and auditors) with direct access should take all rea sonable
p.000007: precautions within the constraints of the applicable regulatory requirement(s) to maintain the
p.000007: confidentiality of subjects' identities and sponsor’s proprietary information.
p.000007:
p.000007: 1.22 Documentation
p.000007: All records, in any form (inclu ding, but not limited to, written, electronic, magnetic, a nd
p.000007: optical records, and scans, x-rays, and electrocardiograms) that describe or record the
p.000007: methods, conduct, and/or results of a trial, the factors affecting a trial, and the action s
p.000007: taken.
p.000007:
p.000007: 1.23 Ess en tial Documents
p.000007: Documents which in divid ually and collectively permit evaluation of the conduct of a study and the
p.000007: quality of the data produced (see 8. Essential Documents for the Conduct of a Clinical T r i a l ) .
p.000007:
p.000007: 1.24 Good Clinical Practice (GCP)
p.000007: A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting
p.000007: of clinical trials that provides assurance that the data and reported results are
p.000007: credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are
p.000007: protected.
p.000007:
p.000007: 1.25 Independent Data-Monitoring Committee (IDMC) ( Data and Safety Monitoring Board, Monitoring Committee,
p.000007: Data
p.000007: Monitoring Committee)
p.000007: An independent data-monitoring committee that may be established by the sponsor to assess at intervals
p.000007: the progress of a clinical trial, the safety data, and the critical efficacy endpoints,
...
p.000020: trial procedures to be followed, including all invasive procedures.
p.000020: e) The subject's responsibilities.
p.000020: f ) Those aspects of the trial that are experimental.
p.000020: g ) The reasonably foreseeable r isks or inconveniences to the subject and, when
p.000020: applicable, to an embryo, foetus, or nursing infant.
p.000020: h) The reasonably expected benefits. When there is no intended clinical benefit to the
p.000020: subject, the subject should be made aware of this.
p.000020: i ) The alternative procedure(s) or course(s) of treatment that may be available to the
p.000020: subject, and their important potential benefits and risks.
p.000020: j ) The compensation and/or treatment available to the subject in the event of trial-related i n j
p.000020: ur y.
p.000020: k ) The anticipated prorated payment, if any, to the subject for participating in the trial. l )
p.000020: The anticipated expenses, if any, to the subject for participating in the trial.
p.000020: m ) That the subject's participation in the trial is voluntary and that the subject may refuse
p.000020: to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which
p.000020: the subject is otherwise entitled.
p.000020: n ) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be
p.000020: granted direct access to the subject's original medical records for verification of clinical
p.000020: trial procedures and /or data, without violating the confidentiality of the subject, to the
p.000020: extent permitted by the applicable laws and regulations and that, by signing a written informed
p.000020: consent form, the subject or the subject's legally acceptable representative is authorising such access.
p.000020: o) That records identifying the subject will be kept confident ial and, to the
p.000020: extent permitted by the applicable laws and/or regulations, will not be made p ublicly
p.000020: available. If the results of the trial are published, the subject’s identity will r e ma i n
p.000020: confide ntial.
p.000020: p) That the subject or the subject's legally acceptable representative will be informed in a t
p.000020: imely manner if information becomes available that may be relevant to the s ubject's willingness to
p.000020: continue participation in the trial.
p.000020: q) The person(s) to contact for further information regarding the trial and the rights of
p.000020: trial subjects, and whom to contact in the event of trial-related injury.
p.000020: r ) The foreseeable circumstances and/or reasons under which the subject's participation in the
p.000020: trial may be terminated.
p.000020: s) The expected duration of the subject's participation in the trial.
p.000020: t) The approximate number of subjects involved in the trial.
p.000020: 4.8.11 Prior to participation in the trial, the subject or the subject's legally
p.000020: acceptable representative should receive a copy of the signed and dated written informed consent fo
p.000020: rm and any other written information provided to the su bjects. During a subject’s participation
p.000020:
p.000021: 21
p.000021:
p.000021: ■ 3CC1a _____________________________________________________________
p.000021:
p.000021:
p.000021:
...
p.000022: retain records of the changes and corrections.
p.000022: 4.9.4 The investigator/institution should maintain the trial documents as specified i n
p.000022: Essential Documents for the Conduct of a Clinical Trial (see 8.) and as required by the
p.000022: applicable regulatory requirement(s). The investigator/institution should take measures to prevent
p.000022: accidental or premature destruction of these documents.
p.000022: 4.9.5 Essential documents should be retained until at least 2 years after the last approval of a
p.000022: marketing application in an ICH region and until there are no pending or contemplated marketing
p.000022: applications in an ICH region or at least 2 years have elapsed since the fo rma l discontinuation
p.000022: of clinical development of the investigational product. These documents should be retained for
p.000022: a longer period however if required by the applicable regulatory requirements or by an
p.000022: agreement with the sponsor. It is the responsibility of the sponsor to inform the
p.000022: investigator/institution as to when these documents no longer need to be retained (see 5.5.12).
p.000022: 4.9.6 The financial aspects of the trial should be documented in an agreement between the sponsor
p.000022: and the investigator/institution.
p.000022: 4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the
p.000022: investigator/institution should make available for direct access all requ ested trial-related recor
p.000022: ds.
p.000022:
p.000022: 4.10 Progress Reports
p.000022: 4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC
p.000022: annually, or more frequently, if requested by the IRB/IEC.
p.000022: 4.10.2 The investigator should promptly provide written rep orts to the sponsor, the IRB/IEC (see
p.000022: 3.3.8) and, where applicable, the institution on any changes significantly affecting the conduct of
p.000022: the trial, and/or increasing the risk to subjects.
p.000022:
p.000022: 4.11 Safety Reporting
p.000022: 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except
p.000022: for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies
p.000022: as not needing immediate reporting. The immediate reports should be followed promptly by
p.000022: detailed, written reports. The immediate and follow-up reports should ide ntify subjects by unique
p.000022: code numbers assigned to the trial subjects rather than by the subjects’ names, personal
p.000022: identification numbers, and/or addresses. The investigator should a l so comply with the applicable
p.000022: regulatory requirement(s) rel ated to the reporting of unexpected serious adverse drug reactions to
p.000022: the regulatory authority(ies) and the IRB/IEC.
p.000022: 4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as cr i t ica l to
...
p.000023: inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or
p.000023: suspension.
p.000023: 4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see
p.000023: 3.1.2 and 3.3.9), the investigator should inform the institution where applicable and the
p.000023: investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed
p.000023: written explanation of the termination or suspension.
p.000023:
p.000023: 4.13 Final Report( s) by Investigator
p.000023: Upon completion of the trial, the investigator, where applicable, should inform the
p.000023: institution; the investigator/institution should provide the IRB/IEC with a summ ary of the trial’s
p.000023: outcome, and the regulatory authority(ies) with any reports required.
p.000023:
p.000023:
p.000023: 5. S PONSOR
p.000023: 5.1 Quality Assurance and Quality Control
p.000023: 5.1.1 The sponsor is responsible for implementing and maintaining quality a ss urance and
p.000023: quality control systems with written SOPs to ensure that trials are conducted and data are generated,
p.000023: documented (recorded), and reported in compliance with the protocol, GCP, and the applicable
p.000023: regulatory requirement(s).
p.000023: 5.1.2 The sponsor is responsible for securing agreement from all involved parties to
p.000023: ensure direct access (see 1.21) to all trial related sites, source data/documents, and reports for
p.000023: the purpose of monitoring and auditing by the sponsor, and inspection by domestic a nd foreign
p.000023: regulatory authorities.
p.000023: 5.1.3 Quality control should be applied to each stage of data handling to ensure that a l l
p.000023: data are reliable and have been processed correctly.
p.000023: 5.1.4 Agreements, made by the sponsor with the investigator/institution and any other parties
p.000023: involved with the clinical trial, should be in writing, as part of the protocol or in a separate
p.000023: agreement.
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000024: 24
p.000024:
p.000024: _____________________________________________________________ 3CC1a ■
p.000024:
p.000024:
p.000024:
p.000024: 5.2 Contract Research Organisation (CRO)
p.000024: 5.2.1 A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a
p.000024: CRO, but the ultimate responsibility for the quality and integrity of the trial data a lw a ys
p.000024: resides with the sponsor. The CRO should implement quality assurance and quality control.
p.000024: 5.2.2 Any trial-related duty and function that is transferred to and assumed by a CRO
p.000024: should be specified in writing.
p.000024: 5.2.3 Any trial-related duties and functions not specifically transferred to and assumed by a CRO are
p.000024: retained by the sponsor.
p.000024: 5.2.4 All references to a sponsor in this guideline also apply to a CRO to the extent that a
p.000024: CRO has assumed the trial related duties and functions of a sponsor.
p.000024:
...
p.000024: overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical
p.000024: analyses, and to prepare the trial reports.
p.000024: 5.5.2 The sponsor may consider establishing an independent data-monitoring committee (IDMC) to
p.000024: assess the progress of a clinical trial, including the safety data and the cr i t ica l efficacy
p.000024: endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or
p.000024: stop a trial. The IDMC should have written operating procedures and maintain written records of all
p.000024: its meetings.
p.000024: 5.5.3 When using electronic trial data handling and/or remote electronic trial data
p.000024: systems, the sponsor should:
p.000024: a) Ensure and document that the electronic data processing system(s) conforms to the
p.000024: sponsor’s established requirements for completeness, accuracy, reliability, a nd consistent
p.000024: intended performance (i.e. validation).
p.000024: b) Maintains SOPs for using these systems.
p.000024:
p.000024:
p.000024:
p.000024:
p.000025: 25
p.000025:
p.000025: ■ 3CC1a _____________________________________________________________
p.000025:
p.000025:
p.000025:
p.000025: c ) Ensure that the systems are designed to permit data changes in such a way that the
p.000025: data changes are documented and that there is no deletion of entered data (i.e.
p.000025: maintain an audit trail, data trail, edit trail).
p.000025: d) Maintain a security system that prevents unauthorised access to the data.
p.000025: e) Maintain a list of the individuals who are authorised to make data changes (see 4.1.5 and
p.000025: 4.9.3).
p.000025: f ) Maintain adequate backup of the data.
p.000025: g ) Safeguard the blinding, if any (e.g. maintain the blinding during data entry a nd p
p.000025: rocessing).
p.000025: 5.5.4 If data are transformed during processing, it should always be possible to com p are the
p.000025: original data and observations with the processed data.
p.000025: 5.5.5 The sponsor should use an unambiguous subject identification c ode (see 1.58) that allows
p.000025: identification of all the data reported for each subject.
p.000025: 5.5.6 The sponsor, or other owners of the data, should retain all of the sponsor-specific
p.000025: essential documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical
p.000025: T r i a l).
p.000025: 5.5.7 The sponsor should retain all sponsor-specific essential documents in conformance with the
p.000025: applicable regulatory requirement(s) of the country(ies) where the product i s approved,
p.000025: and/or where the sponsor intends to apply for approval(s).
p.000025: 5.5.8 If the sponsor discontinues the clinical development of an investigational product (i.e.
p.000025: for any or all indications, routes of administration, or dosage forms), the sponsor should
p.000025: maintain all sponsor-specific essential documents for at least 2 years after fo rma l
p.000025: discontinuation or in conformance with the applicable regulatory requirement(s).
...
p.000028: unused investigational product(s) to the sponsor (or alternative disposition i f authorised by the
p.000028: sponsor and in compliance with the applicable regulatory requirement(s)).
p.000028: 5.14.4 The sponsor should:
p.000028: a) Ensure timely delivery of investigational product(s) to the investigator(s).
p.000028: b) Maintain records that document shipment, receipt, disposition, return, and destruction of the
p.000028: investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical T r i a
p.000028: l).
p.000028: c ) Maintain a system for retrieving investigational products and documenting this
p.000028: retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product
p.000028: reclaim).
p.000028: d) Maintain a system for the disposition of unused investigational product(s) and for the
p.000028: documentation of this disposition.
p.000028: 5.14.5 The sponsor should:
p.000028: a) Take steps to ensure that the investigational product(s) are stable over the period of use.
p.000028: b) Maintain sufficient quantities of the investigational product(s) used in the trials to
p.000028: reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and
p.000028: characteristics. To the extent stability permits, samples should be
p.000028: retained either until the analyses of the trial data are complete or as required by the applicable
p.000028: regulatory requirement(s), whichever represents the longer retention period.
p.000028:
p.000028: 5.15 R ecord Access
p.000028: 5.15.1 The sponsor should ensure that it is specified in the protocol or other written
p.000028: agreement that the investigator(s)/institution(s) provide direct access to
p.000028: source
p.000028:
p.000028:
p.000029: 29
p.000029:
p.000029: ■ 3CC1a _____________________________________________________________
p.000029:
p.000029:
p.000029:
p.000029: data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory
p.000029: inspection.
p.000029: 5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to
p.000029: his/her original medical records for trial-related monitoring, audit, IRB/IEC review, a nd regulatory
p.000029: inspection.
p.000029:
p.000029: 5.16 Safe ty Informa tio n
p.000029: 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the inves tigational
p.000029: product(s).
p.000029: 5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) a nd the
p.000029: regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact
p.000029: the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial.
p.000029:
p.000029: 5.17 Adverse Drug Reaction Reporting
p.000029: 5.17.1 The sponsor should expedite the reporting to all
p.000029: conce rn ed investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the
p.000029: regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected.
p.000029: 5.17.2 Such expedited reports should co mply with the applicable regulatory requir ement(s) and with
p.000029: the note for guidance on Clinical Safety Data Management: Definitions and Standards for
p.000029: Expedited Reporting .
p.000029: 5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates a nd
...
p.000032: protocol, SOPs, GCP, and the applicable regulatory requirements.
p.000032:
p.000032: 5.19.2 Selection and Qualification of Auditors
p.000032: a) The sponsor should appoint individuals, who are independent of the cli n ic a
p.000032: l trials/systems, to conduct audits.
p.000032: b) The sponsor should ensure that the auditors are qualified by training and experience to conduct
p.000032: audits properly. An auditor’s qualifications should be documented.
p.000032:
p.000032: 5.19.3 Au d iting Proced ures
p.000032: a) The sponsor should ensure that the audi t ing of clinical trials/systems is conducted i n
p.000032: accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of
p.000032: audits, and the form and content of audit reports.
p.000032: b) The sponsor's audit plan and procedures for a trial audit should be guided by the
p.000032: importance of the trial to submissions to regulatory authorities, the number of subjects in the trial,
p.000032: the type and complexity of the trial, the level of risks to the trial subjects, and any identified
p.000032: problem(s).
p.000032: c ) The observations and findings of the auditor(s) should be documented.
p.000032: d) To preserve the independence and value of the audit function, the regulatory
p.000032: authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek
p.000032: access to an audit report on a case by case basis when evidence of se r iou s GCP non-compliance
p.000032: exists, or in the course of legal proceedings.
p.000032: e) When required by applicable law or regulation, the sponsor should provide an audit
p.000032: certificate.
p.000032:
p.000033: 33
p.000033:
p.000033: ■ 3CC1a _____________________________________________________________
p.000033:
p.000033:
p.000033:
p.000033:
p.000033: 5.20 Noncomp li ance
p.000033: 5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory
p.000033: requirement(s) by an investigator/institution, or by member(s) of the sponsor’s staff should lead to
p.000033: prompt action by the sponsor to secure compliance.
p.000033: 5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part
p.000033: of an investigator/institution, the sponsor should terminate the inves tigator’s/ institution’s
p.000033: participation in the trial. When an investigator’s/institution’s participation i s
p.000033: terminated because of noncompliance, the sponsor should notify promptly the regulatory
p.000033: authority(ies).
p.000033:
p.000033: 5.21 Premature Termination or Suspension of a Trial
p.000033: If a trial is prematurely terminated or suspended, the sponsor should promptly inform the
p.000033: investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the
p.000033: reason(s) for the termination or suspension. The IRB/IEC should also be i nform ed promptly and provided
...
p.000036: 6.8 Assessment of Safety
p.000036: 6.8.1 Specification of safety parameters.
p.000036: 6.8.2 The methods and t iming for assessing, recording, and analysing safety parameters.
p.000036: 6.8.3 Procedures for eliciting reports of and for recording and reporting adverse event a nd
p.000036: intercurrent illnesses.
p.000036: 6.8.4 The type and duration of the follow-up of subjects after adverse events.
p.000036:
p.000036:
p.000036: 6.9 Statistics
p.000036: 6.9.1 A description of the statistical methods to be employed, including t iming of a ny
p.000036: planned interim analysis(ses).
p.000036: 6.9.2 The number of subjects planned to be enrolled. In multicentre trials, the numbers of
p.000036: enrolled subjects projected for each trial site should be specified. Reason for choice of s am ple size,
p.000036: including reflections on (or calculations of) the power of the trial and cli n ic a l ju
p.000036: s t ification.
p.000036: 6.9.3 The level of significance to be used.
p.000036: 6.9.4 Criteria for the termination of the trial.
p.000036: 6.9.5 Procedure for accounting for missing, unused, and spurious data.
p.000036: 6.9.6 Procedures for reporting any deviation(s) from the original statistical plan ( an y
p.000036: deviation(s) from the original statistical plan should be described and justified in protocol and/or
p.000036: in the final report, as appropriate).
p.000036: 6.9.7 The selection of subjects to be included in the analyses (e.g. all randomised subjects, all
p.000036: dosed subjects, all eligible subjects, evaluable subjects).
p.000036:
p.000036: 6.10 Dir ect Access to Source Data/Documents
p.000036: The sponsor should ensure that it is specified in the protocol or other written agreement that the
p.000036: investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and
p.000036: regulatory inspection(s), providing direct access to source data/documents.
p.000036:
p.000036: 6.11 Quality Control and Quality Assurance
p.000036:
p.000036:
p.000036:
p.000036:
p.000036:
p.000037: 37
p.000037:
p.000037: ■ 3CC1a _____________________________________________________________
p.000037:
p.000037:
p.000037:
p.000037: 6.12 Et h ics
p.000037: Description of ethical considerations relating to the trial.
p.000037:
p.000037:
p.000037: 6.13 Data Handling and Record Keeping
p.000037:
p.000037: 6.14 Financing and Insurance
p.000037: Financing and insurance if not addressed in a separate agreement.
p.000037:
p.000037:
p.000037: 6.15 Pu blication P olicy
p.000037: Publication policy, if not addressed in a separate agreement.
p.000037:
p.000037:
p.000037: 6.16 Supp l emen ts
p.000037: (NOTE: Since the protocol and the clinical trial/study report are closely related, further
p.000037: relevant information can be found in the note for guidance on Structure and Content o f
p.000037: Clinical S tudy Reports .)
p.000037:
p.000037:
p.000037: 7. INVESTIGATOR’S BROCHURE
p.000037: 7.1 I n trod uc tio n
p.000037: The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the
p.000037: investigational product(s) that are relevant to the study of the product(s) in human subjects. Its
p.000037: purpose is to provide the investigators and others involved in the trial with the
p.000037: information to facilitate their understanding of the rationale for, and their compliance with, many
p.000037: key features of the protocol, such as the dose, dose frequency/interval, methods of administration,
...
p.000050: assessment or
p.000050: – other validation (where required)
p.000050: To document that tests remain adequate throughout the trial
p.000050: period (see 8.2.12)
p.000050: X X
p.000050: (where
p.000050: required)
p.000050:
p.000050: 8.3.8 DOCUMENTATION OF INVESTIGATIONAL
p.000050: P RODUCT( S) AND TRIAL- RELATED MATERIALS
p.000050: SH I P M EN T
p.000050: 8.3.9 CERTIFICATE( S) OF ANALYSIS FOR NEW BATCHES OF
p.000050: INVESTIGATIONAL P RODUCTS
p.000050: (see 8.2.15.) X X
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050: (see 8.2.16) X
p.000050: 8.3.10 MONITORING VISIT RE PORTS To document site visits by, and
p.000050: X
p.000050: findings of, the monitor
p.000050:
p.000050: 8.3.11 RELEVANT COMMUNICATIONS OTHER THAN SITE VISITS
p.000050: – letters
p.000050: – meeting notes
p.000050: – notes of telephone calls
p.000050: 8.3.12 SIGNED INFORMED CONSENT F O RM S
p.000050: To document any agreements or X X significant discu ssion s
p.000050: regarding trial administration, protocol violations, trial conduct, adverse event (AE) reporting
p.000050:
p.000050: To document that consent is X obtained in accordance with GCP
p.000050: and protocol and dated prior to participation of each subject in trial. Also to document direct
p.000050: access permission (see 8.2.3)
p.000050: 8.3.13 SOURCE DOCUMENTS To document the existence of the X
p.000050: subject and substantiate integrity of trial data collected. To include original documents related to the
p.000050: trial, to medical treatment, and
p.000050: history of subject
p.000050:
p.000050: 8.3.14 SIGNED, DATED AND
p.000050: COMPLETED CASE RE PORT FORMS (CRF)
p.000050: To document that the investigator or authorised member of the
p.000050: investigator’s staff confirms the observations recorded
p.000050: X
p.000050: (copy)
p.000050: X
p.000050: (or igi na l)
p.000050:
p.000050:
p.000050:
p.000050:
p.000051: 51
p.000051:
p.000051: ■ 3CC1a _____________________________________________________________
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: Titl e of Document Pu rpose
p.000051: Located i n Files of
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: 8.3.15 DOCUMENTATION OF CRF CORRECTIONS
p.000051:
p.000051:
p.000051:
p.000051: To document all changes/
p.000051: additions or corrections made to CRF after initial data were
p.000051: recorded
p.000051: Investigator/ I ns tit u tio n
p.000051: X
p.000051: (copy)
p.000051: Sponso r
p.000051:
p.000051:
p.000051: X
p.000051: (or igi na l)
p.000051:
p.000051: 8.3.16 NOTIFICATION BY
p.000051: ORIGINATING INVESTIGATOR TO S PONSOR OF SERIOUS
p.000051: ADVERSE EVENTS AND RELATED REPORTS
p.000051: Notification by originating X X investigator to
p.000051: sponsor of serious
p.000051: adverse events and related reports in accordance with 4.11
p.000051:
p.000051: 8.3.17 NOTIFICATION BY S PONSOR AND/OR INVESTIGATOR,
...
Social / Age
Searching for indicator age:
(return to top)
p.000034: amendment number(s) and date(s).
p.000034: 6.1.2 Name and address of the sponsor and monitor (if other than the sponsor).
p.000034: 6.1.3 Name and title of the person(s) authorised to sign the protocol and the
p.000034: protocol amendment(s) for the sponsor.
p.000034: 6.1.4 Name, title, address, and telephone number(s) of the sponsor's medical expert (or
p.000034: dentist when appropriate) for the trial.
p.000034: 6.1.5 Name and title of the investigator(s) who is (are) responsible for conducting the tr i a l,
p.000034: and the address and telephone number(s) of the trial site(s).
p.000034: 6.1.6 Name, title, address, and telephone number(s) of the qualified physician (or dentist, if
p.000034: applicable), who is responsible for all trial-site related medical (or dental) decisions ( i f
p.000034: other than investigator).
p.000034: 6.1.7 Na me(s) and address(es) of the clinical laboratory(ies) and other medical and/or
p.000034: technical department(s) and/or institutions involved in the trial.
p.000034:
p.000034: 6.2 Background Infor ma tio n
p.000034: 6.2.1 Name and description of the investigational product(s).
p.000034: 6.2.2 A s ummary of findings from nonclinical studies that potentially have cli n ic a l
p.000034: significance and from clinical trials that are relevant to the trial.
p.000034: 6.2.3 Summary of the known and potential risks and benefits, if any, to human subjects.
p.000034: 6.2.4 Description of, and justification for, the route of administration, dosage, dos age
p.000034: regimen, and treatment period(s).
p.000034: 6.2.5 A statement that the trial will be conducted in compliance with the protocol, GCP a nd the
p.000034: applicable regulatory requirement(s).
p.000034: 6.2.6 Description of the population to be studied.
p.000034: 6.2.7 References to literature and data that are relevant to the trial, and that
p.000034: provide background for the trial.
p.000034:
p.000034: 6.3 Trial Objectives and Purpose
p.000034: A detailed description of the objectives and the purpose of the trial.
p.000034:
p.000034:
p.000034:
p.000034:
p.000035: 35
p.000035:
p.000035: ■ 3CC1a _____________________________________________________________
p.000035:
p.000035:
p.000035:
p.000035: 6.4 Trial Design
p.000035: The scientific integrity of the trial and the credibility of the data from the trial depend
p.000035: substantially on the trial design. A description of the trial design, should include:
p.000035: 6.4.1 A specific statement of the primary endpoints and the secondary endpoints, if any, to be
p.000035: measured during the trial.
p.000035: 6.4.2 A description of the type/design of trial to be conducted (e.g. double-blind, placebo-
p.000035: controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
p.000035: 6.4.3 A description of the measures taken to minimise/avoid bias, including: a) R an domis ation.
p.000035: b) Bli n d i n g.
p.000035: 6.4.4 A description of the trial treatment(s) and the dosage and dosage regimen of the
...
p.000040: – C arcinogenicity
p.000040: – Special studies (e.g. irritancy and sensitisation)
p.000040: – Reproductive toxicity
p.000040: – Genotoxicity (mutagenicity)
p.000040:
p.000040: 7.3.6 Effects in Hu ma ns
p.000040: Introduction:
p.000040: A thorough discussion of the known effects of the investigational product(s) in human s should
p.000040: be provided, including information on pharmacokinetics, metabolis m,
p.000040: pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where
p.000040: possible, a summary of each completed clinical trial should be provided. I nformation should also be
p.000040: provided regarding results of any use of the investigational product(s) other than from in clinical
p.000040: trials, such as from experience during marketing.
p.000040:
p.000040:
p.000041: 41
p.000041:
p.000041: ■ 3CC1a _____________________________________________________________
p.000041:
p.000041:
p.000041:
p.000041: a) Pharmacokinetics and Product Metabolism in Humans
p.000041: – A summary of information on the pharmacokinetics of the inves tigational product(s)
p.000041: should be presented, including the following, if available:
p.000041: – Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma
p.000041: protein binding, distribution, and elimination).
p.000041: – Bioavailability of the investigational product (absolute, where possible, and/or relative)
p.000041: using a reference dosage form.
p.000041: – Population subgroups (e.g., gender, age, and impaired organ function).
p.000041: – Interactions (e.g., product-product interactions and effects of food).
p.000041: – Other pharmacokinetic data (e.g., results of population studies performed within clinical
p.000041: trial(s).
p.000041: b) Safety and Efficacy
p.000041: A summary of information should be provided about the inves tigational
p.000041: product’s/products’ (inclu ding metabolites, where appropriate) safety, pharmaco- dynamics,
p.000041: efficacy, and dose response that were obtained from preceding trials i n humans (healthy
p.000041: volunteers and/or patients). The implications of this i nformat ion should be discussed. In cases
p.000041: where a number of clinical trials have been completed, the use of summaries of safety and
p.000041: efficacy across multiple trials by indications i n subgroups may provide a clear presentation of the
p.000041: data. Tabular summaries of a dver se drug reactions for all the clinical trials (inclu
p.000041: ding those for all the studied indications) would be useful. Important differences
p.000041: in adverse drug reaction patterns/incidences across indications or subgroups should be discussed.
p.000041: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated
...
Social / Ethnicity
Searching for indicator ethnic:
(return to top)
p.000012: An adverse reaction, the nature or severity of which is not consistent with the applicable
p.000012: product information (e.g., Investigator's Brochure for an unapproved investigational product or package
p.000012: insert/summary of product characteristics for an a pproved product) (see note for guidance on Clinical
p.000012: Safety Data Management: Definitions and Standards for Expedited Reporting ).
p.000012:
p.000012: 1.61 Vulnerable Subjec ts
p.000012: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
p.000012: expectation, whether justified or not, of benefits associated with participation, or of a
p.000012: retaliatory response from senior members of a hierarchy in case of refusal to participate.
p.000012: Examples are members of a group with a hierarchical structure, such as medical, p harmacy, dental, and
p.000012: nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
p.000012: industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
p.000012: include patients with in curable diseases, persons in nur s i n g homes, unemployed or
p.000012: impoverished persons, patients in emergency situations, ethnic minority groups, homeless
p.000012: persons, nomads, refugees, minors, and those incapable of giving consent.
p.000012:
p.000012: 1.62 Well-being ( of the trial subjects)
p.000012: The physical and mental integrity of the subjects participating in a clinical trial.
p.000012:
p.000012:
p.000012:
p.000012: 2. THE PRINCIPLES OF ICH GCP
p.000012: 2.1 Clinical trials should be conducted in accordance with the ethical principles that
p.000012: have their origin in the Declaration of Helsinki, and that are consistent with GCP and the
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
p.000012: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000012: considerations and should prevail over interests of science and society.
p.000012: 2.4 The available nonclinical and clinical information on an investigational product
p.000012: should be adequate to support the proposed clinical trial.
p.000012:
p.000012:
p.000013: 13
p.000013:
p.000013: ■ 3CC1a _____________________________________________________________
p.000013:
p.000013:
p.000013:
...
Social / Fetus/Neonate
Searching for indicator foetus:
(return to top)
p.000019: information in the consent form and any other written information was accurately
p.000019: explained to, and apparently understood by, the subject or the subject's legally acceptable
p.000019: representative, and that informed consent was freely given by the subject or the subject’s
p.000019: legally acceptable representative.
p.000019: 4.8.10 Both the informed consent discussion and the written informed consent form a nd any
p.000019: other written information to be provided to subjects should include explanations of the followi n g:
p.000019:
p.000020: 20
p.000020:
p.000020: _____________________________________________________________ 3CC1a ■
p.000020:
p.000020:
p.000020:
p.000020: a) That the trial involves research.
p.000020: b) The purpose of the trial.
p.000020: c ) The trial treatment(s) and the probability for random assignment to each treatment. d) The
p.000020: trial procedures to be followed, including all invasive procedures.
p.000020: e) The subject's responsibilities.
p.000020: f ) Those aspects of the trial that are experimental.
p.000020: g ) The reasonably foreseeable r isks or inconveniences to the subject and, when
p.000020: applicable, to an embryo, foetus, or nursing infant.
p.000020: h) The reasonably expected benefits. When there is no intended clinical benefit to the
p.000020: subject, the subject should be made aware of this.
p.000020: i ) The alternative procedure(s) or course(s) of treatment that may be available to the
p.000020: subject, and their important potential benefits and risks.
p.000020: j ) The compensation and/or treatment available to the subject in the event of trial-related i n j
p.000020: ur y.
p.000020: k ) The anticipated prorated payment, if any, to the subject for participating in the trial. l )
p.000020: The anticipated expenses, if any, to the subject for participating in the trial.
p.000020: m ) That the subject's participation in the trial is voluntary and that the subject may refuse
p.000020: to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which
p.000020: the subject is otherwise entitled.
p.000020: n ) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be
p.000020: granted direct access to the subject's original medical records for verification of clinical
p.000020: trial procedures and /or data, without violating the confidentiality of the subject, to the
p.000020: extent permitted by the applicable laws and regulations and that, by signing a written informed
...
Social / Homeless Persons
Searching for indicator homeless:
(return to top)
p.000012: product information (e.g., Investigator's Brochure for an unapproved investigational product or package
p.000012: insert/summary of product characteristics for an a pproved product) (see note for guidance on Clinical
p.000012: Safety Data Management: Definitions and Standards for Expedited Reporting ).
p.000012:
p.000012: 1.61 Vulnerable Subjec ts
p.000012: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
p.000012: expectation, whether justified or not, of benefits associated with participation, or of a
p.000012: retaliatory response from senior members of a hierarchy in case of refusal to participate.
p.000012: Examples are members of a group with a hierarchical structure, such as medical, p harmacy, dental, and
p.000012: nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
p.000012: industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
p.000012: include patients with in curable diseases, persons in nur s i n g homes, unemployed or
p.000012: impoverished persons, patients in emergency situations, ethnic minority groups, homeless
p.000012: persons, nomads, refugees, minors, and those incapable of giving consent.
p.000012:
p.000012: 1.62 Well-being ( of the trial subjects)
p.000012: The physical and mental integrity of the subjects participating in a clinical trial.
p.000012:
p.000012:
p.000012:
p.000012: 2. THE PRINCIPLES OF ICH GCP
p.000012: 2.1 Clinical trials should be conducted in accordance with the ethical principles that
p.000012: have their origin in the Declaration of Helsinki, and that are consistent with GCP and the
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
p.000012: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000012: considerations and should prevail over interests of science and society.
p.000012: 2.4 The available nonclinical and clinical information on an investigational product
p.000012: should be adequate to support the proposed clinical trial.
p.000012:
p.000012:
p.000013: 13
p.000013:
p.000013: ■ 3CC1a _____________________________________________________________
p.000013:
p.000013:
p.000013:
p.000013: 2.5 Clinical trials should be scientifically sound, and described in a clear,
p.000013: detailed protocol.
...
Social / Infant
Searching for indicator infant:
(return to top)
p.000019: information in the consent form and any other written information was accurately
p.000019: explained to, and apparently understood by, the subject or the subject's legally acceptable
p.000019: representative, and that informed consent was freely given by the subject or the subject’s
p.000019: legally acceptable representative.
p.000019: 4.8.10 Both the informed consent discussion and the written informed consent form a nd any
p.000019: other written information to be provided to subjects should include explanations of the followi n g:
p.000019:
p.000020: 20
p.000020:
p.000020: _____________________________________________________________ 3CC1a ■
p.000020:
p.000020:
p.000020:
p.000020: a) That the trial involves research.
p.000020: b) The purpose of the trial.
p.000020: c ) The trial treatment(s) and the probability for random assignment to each treatment. d) The
p.000020: trial procedures to be followed, including all invasive procedures.
p.000020: e) The subject's responsibilities.
p.000020: f ) Those aspects of the trial that are experimental.
p.000020: g ) The reasonably foreseeable r isks or inconveniences to the subject and, when
p.000020: applicable, to an embryo, foetus, or nursing infant.
p.000020: h) The reasonably expected benefits. When there is no intended clinical benefit to the
p.000020: subject, the subject should be made aware of this.
p.000020: i ) The alternative procedure(s) or course(s) of treatment that may be available to the
p.000020: subject, and their important potential benefits and risks.
p.000020: j ) The compensation and/or treatment available to the subject in the event of trial-related i n j
p.000020: ur y.
p.000020: k ) The anticipated prorated payment, if any, to the subject for participating in the trial. l )
p.000020: The anticipated expenses, if any, to the subject for participating in the trial.
p.000020: m ) That the subject's participation in the trial is voluntary and that the subject may refuse
p.000020: to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which
p.000020: the subject is otherwise entitled.
p.000020: n ) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be
p.000020: granted direct access to the subject's original medical records for verification of clinical
p.000020: trial procedures and /or data, without violating the confidentiality of the subject, to the
p.000020: extent permitted by the applicable laws and regulations and that, by signing a written informed
p.000020: consent form, the subject or the subject's legally acceptable representative is authorising such access.
...
Social / Linguistic Proficiency
Searching for indicator language:
(return to top)
p.000018:
p.000019: 19
p.000019:
p.000019: ■ 3CC1a _____________________________________________________________
p.000019:
p.000019:
p.000019:
p.000019: 4.8.2 The written informed consent form and any other written information to be provided to
p.000019: subjects should be revised whenever important new information becomes available that may be
p.000019: relevant to the subject’s consent. Any revised written informed consent form, a nd written
p.000019: information should receive the IRB/IEC's approval/favourable opinion in advance of use. The subject or the
p.000019: subject’s legally acceptable representative should be informed in a t imely manner if new
p.000019: information becomes available that may be relevant to the subject’s willingness to continue
p.000019: participation in the trial. The communication of this i nformat ion should be documented.
p.000019: 4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a
p.000019: subject to participate or to continue to participate in a trial.
p.000019: 4.8.4 None of the oral and written information concerning the trial, including the written informed
p.000019: consent form, should contain any language that causes the subject or the subject’s legally
p.000019: acceptable representative to waive or to appear to waive any legal rights, or that releases
p.000019: or appears to release the investigator, the institution, the sponsor, or their agents from
p.000019: liability or negligence.
p.000019: 4.8.5 The investigator, or a person designated by the investigator, should fully inform the
p.000019: subject or, if the subject is unable to provide informed consent, the subject’s leg a
p.000019: lly acceptable representative, of all pertinent aspects of the trial including the
p.000019: written information and the approval/favourable opinion by the IRB/IEC.
p.000019: 4.8.6 The language u sed in the oral and written information about the trial, including the
p.000019: written informed consent form, should be as non-technical as practical and should be
p.000019: understandable to the subject or the subject's legally acceptable representative and the
p.000019: impartial witness, where applicable.
p.000019: 4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the
p.000019: investigator, should provide the subject or the subject's legally acceptable representative ample time
p.000019: and opportunity to inquire about details of the trial and to decide whether or not to
p.000019: participate in the trial. All questions about the trial should be answered to the satisfaction of
p.000019: the subject or the subject's legally acceptable representative.
p.000019: 4.8.8 Prior to a subject’s participation in the trial, the written informed consent fo rm
p.000019: should be signed and personally dated by the subject or by the subject's legally acceptable
p.000019: representative, and by the person who conducted the informed consent discussion.
p.000019: 4.8.9 If a subject is unable to read or if a legally acceptable representative is unable
p.000019: to read, an impartial witness should be present during the entire informed consent discu ssion. After
...
Social / Marital Status
Searching for indicator single:
(return to top)
p.000005: See Protocol Amendment.
p.000005:
p.000005:
p.000005: 1.4 Applicabl e R egulatory R e q u ir emen t( s)
p.000005: Any law(s) and regulation(s) addressing the conduct of clinical trials of inves tigational
p.000005: products.
p.000005:
p.000005: 1.5 Approval (in relation to Institutional Revie w Boards)
p.000005: The affirmative decision of the IRB that the clinical trial has been reviewed and may be
p.000005: conducted at the institution site within the constraints set forth by the IRB, the institution, Good
p.000005: Clinical Practice (GCP), and the applicable regulatory requirements.
p.000005:
p.000005: 1.6 A ud it
p.000005: A systematic and independent examination of trial related activities and documents to
p.000005: determine whether the evaluated trial related activities were conducted, and the data were recorded,
p.000005: analysed and accurately reported according to the protocol, sponsor’s s tan d ar d operating
p.000005: procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
p.000005:
p.000005: 1.7 Aud it Certificate
p.000005: A declaration of confirmation by the auditor that an audit has taken place.
p.000005:
p.000005:
p.000005: 1.8 Aud it R eport
p.000005: A written evaluation by the sponsor's auditor of the results of the audit.
p.000005:
p.000005:
p.000005: 1.9 Aud it Trail
p.000005: Documentation that allows reconstruction of the course of events.
p.000005:
p.000005:
p.000005: 1.10 B li nd i ng/Masking
p.000005: A procedure in which one or more parties to the trial are kept unaware of the treatment
p.000005: assignment(s). Single-blinding usua lly refers to the subject(s) being unaware, and double- blinding
p.000005: usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s)
p.000005: being unaware of the treatment assignment(s).
p.000005:
p.000005: 1.11 Case Report Form (CRF)
p.000005: A printed, optical, or electronic document designed to record all of the protocol required
p.000005: information to be reported to the sponsor on each trial subject.
p.000005:
p.000005:
p.000005:
p.000005:
p.000005:
p.000005:
p.000006: 6
p.000006:
p.000006: _____________________________________________________________ 3CC1a ■
p.000006:
p.000006:
p.000006:
p.000006: 1.12 Cli n ical Trial/Study
p.000006: Any investigation in human subjects intended to discover or verify the cli n ic a
p.000006: l, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to
p.000006: identify any adverse reactions to an investigational product(s), and/or to study absorption,
p.000006: distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining
p.000006: its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.
p.000006:
p.000006: 1.13 Cli n ical Trial/Study R eport
p.000006: A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted
p.000006: in human subjects, in which the clinical and statistical description, presentations, and analyses are
p.000006: fully integrated into a single report (see note for guidance on S tructure and Content of Clinical
p.000006: S tudy Reports ).
p.000006:
p.000006: 1.14 Comparator ( P roduct)
p.000006: An investigational or marketed product (i.e., active control), or placebo, used as a r efe r e nce in
p.000006: a clinical trial.
p.000006:
p.000006: 1.15 Compliance ( in relation to trials)
p.000006: Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirement s, and the
p.000006: applicable regulatory requirements.
p.000006:
p.000006: 1.16 Confid en tiality
p.000006: Prevention of disclosure, to other than authorised individuals, of a sponsor's proprietary
p.000006: information or of a subject’s identity.
p.000006:
p.000006: 1.17 Contract
p.000006: A written, dated, and signed agreement between two or more involved parties that sets out any
p.000006: arrangements on delegation and distribution of tasks and obligations and, i f
p.000006: appropriate, on financial matters. The protocol may serve as the basis of a contract.
p.000006:
p.000006: 1.18 Co-ordinating Committee
p.000006: A committee that a sponsor may organise to co-ordinate the conduct of a multicentre trial.
p.000006:
p.000006:
p.000006: 1.19 Co-ordinating Investigator
p.000006: An investigator assigned the responsibility for the co-ordination of investigators at different centres
p.000006: participating in a multicentre trial.
p.000006:
p.000006: 1.20 Contract Research Organisation (CRO)
p.000006: A person or an organisation (commercial, academic, or other) contracted by the sponsor to perform
p.000006: one or more of a sponsor’s trial-related duties and functions.
p.000006:
...
p.000009: by a team of individuals at a trial site, the investigator is the responsible leader of the team
p.000009: and may be called the principal investigator. See also Subinvestigator.
p.000009:
p.000009: 1.35 Investigator / Institution
p.000009: An expression meaning “the investigator and/or institution, where required by the
p.000009: applicable regulatory requirements”.
p.000009:
p.000009: 1.36 Investigator’s Brochure
p.000009: A compilation of the clinical and nonclinical data on the investigational product(s) which i s relevant
p.000009: to the study of the investigational product(s) in human subjects (see 7. Investigator’s Brochure).
p.000009:
p.000009: 1.37 Legally Acceptable Representative
p.000009: An individual or juridical or other body authorised under applicable law to consent, o n behalf
p.000009: of a prospective subject, to the subject’s participation in the clinical trial.
p.000009:
p.000009: 1.38 Monito ri ng
p.000009: The act of overseeing the progress of a clinical trial, and of ensuring that it is con ducted,
p.000009: recorded, and reported in acc ordance with the protocol, Standard Operating Procedures (SOPs),
p.000009: Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
p.000009:
p.000009: 1.39 Monitoring Report
p.000009: A written report from the monitor to the sponsor after each site visit and/or other trial-related
p.000009: communication according to the sponsor’s SOPs.
p.000009:
p.000009: 1.40 Multicentre Trial
p.000009: A clinical trial conducted according to a single protocol but at more than one site, a nd
p.000009: therefore, carried out by more than one investigator.
p.000009:
p.000009: 1.41 Noncli n ical Study
p.000009: Biomedical studies not performed on human subjects.
p.000009:
p.000009:
p.000009: 1.42 Opinion ( in relation to Independent Ethics Committee)
p.000009: The judgement and/or the advice provided by an Independent Ethics Committee (IEC).
p.000009:
p.000009:
p.000009: 1.43 Origi nal Med ical R ecord
p.000009: See Source Documents.
p.000009:
p.000009:
p.000010: 10
p.000010:
p.000010: _____________________________________________________________ 3CC1a ■
p.000010:
p.000010:
p.000010:
p.000010: 1.44 P r otoco l
p.000010: A document that describes the object ive(s), design, methodology, statistical consi de ration s, and
p.000010: organisation of a trial. The protocol usually also gives the background and rationale for the trial, but
p.000010: these could be provided in other protocol referenced documents. Throughout the GCP Guideline the term
p.000010: protocol refers to protocol and protocol amendments.
p.000010:
p.000010: 1.45 P rotocol Amendmen t
p.000010: A written description of a change(s) to or formal clarification of a protocol.
p.000010:
p.000010:
p.000010: 1.46 Quality Assurance (QA)
p.000010: All those planned and systematic actions that are established to ensure that the trial i s
p.000010: performed and the data are generated, documented (recorded), and reported in com pli ance with Good
p.000010: Clinical Practice (GCP) and the applicable regulatory requirement(s).
p.000010:
...
p.000040: species should be compared (i.e., the therapeutic index should be discussed). The relevance of
p.000040: this information to the proposed human dosing should be addressed. Whenever possible, comparisons
p.000040: should be made in terms of blood/tissue levels rather than on a m g / k g ba sis.
p.000040: a) Nonclinical Pharmacology
p.000040: A summary of the pharmacological aspects of the investigational product and, where appropriate, its
p.000040: significant metabolites studied in animals, should be included. Such a summary should incorporate
p.000040: studies that assess potential therapeutic activity (e.g. efficacy models, receptor binding, and
p.000040: specificity) as well as those that assess safety (e.g., special studies to assess
p.000040: pharmacological actions other than the inten ded therapeutic effect(s)).
p.000040: b) Pharmacokinetics and Product Metabolism in Animals
p.000040: A summary of the pharmacokinetics and biological transformation and disposition of the investigational
p.000040: product in all species studied should be given. The discussion of the
p.000040: findings should address the absorption and the local and systemic bioavailability of the
p.000040: investigational product and its metabolites, and their relationship to the
p.000040: pharmacological and toxicological findings in animal species.
p.000040: c ) Toxicology
p.000040: A summary of the toxicological effects found in relevant studies conducted in different animal species
p.000040: should be described under the following headings where appropriate:
p.000040: – Single dose
p.000040: – Repeated dose
p.000040: – C arcinogenicity
p.000040: – Special studies (e.g. irritancy and sensitisation)
p.000040: – Reproductive toxicity
p.000040: – Genotoxicity (mutagenicity)
p.000040:
p.000040: 7.3.6 Effects in Hu ma ns
p.000040: Introduction:
p.000040: A thorough discussion of the known effects of the investigational product(s) in human s should
p.000040: be provided, including information on pharmacokinetics, metabolis m,
p.000040: pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where
p.000040: possible, a summary of each completed clinical trial should be provided. I nformation should also be
p.000040: provided regarding results of any use of the investigational product(s) other than from in clinical
p.000040: trials, such as from experience during marketing.
p.000040:
p.000040:
p.000041: 41
p.000041:
p.000041: ■ 3CC1a _____________________________________________________________
p.000041:
p.000041:
p.000041:
p.000041: a) Pharmacokinetics and Product Metabolism in Humans
p.000041: – A summary of information on the pharmacokinetics of the inves tigational product(s)
p.000041: should be presented, including the following, if available:
p.000041: – Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma
p.000041: protein binding, distribution, and elimination).
p.000041: – Bioavailability of the investigational product (absolute, where possible, and/or relative)
p.000041: using a reference dosage form.
...
Social / Presence of Coercion
Searching for indicator coerce:
(return to top)
p.000018: have their origin in the Declaration of Helsinki. Prior to the beginning of the
p.000018: trial, the investigator should have the IRB/IEC's written approval/favourable opinion of the written
p.000018: informed consent form and any other written information to be provided to subjects.
p.000018:
p.000019: 19
p.000019:
p.000019: ■ 3CC1a _____________________________________________________________
p.000019:
p.000019:
p.000019:
p.000019: 4.8.2 The written informed consent form and any other written information to be provided to
p.000019: subjects should be revised whenever important new information becomes available that may be
p.000019: relevant to the subject’s consent. Any revised written informed consent form, a nd written
p.000019: information should receive the IRB/IEC's approval/favourable opinion in advance of use. The subject or the
p.000019: subject’s legally acceptable representative should be informed in a t imely manner if new
p.000019: information becomes available that may be relevant to the subject’s willingness to continue
p.000019: participation in the trial. The communication of this i nformat ion should be documented.
p.000019: 4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a
p.000019: subject to participate or to continue to participate in a trial.
p.000019: 4.8.4 None of the oral and written information concerning the trial, including the written informed
p.000019: consent form, should contain any language that causes the subject or the subject’s legally
p.000019: acceptable representative to waive or to appear to waive any legal rights, or that releases
p.000019: or appears to release the investigator, the institution, the sponsor, or their agents from
p.000019: liability or negligence.
p.000019: 4.8.5 The investigator, or a person designated by the investigator, should fully inform the
p.000019: subject or, if the subject is unable to provide informed consent, the subject’s leg a
p.000019: lly acceptable representative, of all pertinent aspects of the trial including the
p.000019: written information and the approval/favourable opinion by the IRB/IEC.
p.000019: 4.8.6 The language u sed in the oral and written information about the trial, including the
p.000019: written informed consent form, should be as non-technical as practical and should be
p.000019: understandable to the subject or the subject's legally acceptable representative and the
p.000019: impartial witness, where applicable.
...
Social / Racial Minority
Searching for indicator minority:
(return to top)
p.000012: An adverse reaction, the nature or severity of which is not consistent with the applicable
p.000012: product information (e.g., Investigator's Brochure for an unapproved investigational product or package
p.000012: insert/summary of product characteristics for an a pproved product) (see note for guidance on Clinical
p.000012: Safety Data Management: Definitions and Standards for Expedited Reporting ).
p.000012:
p.000012: 1.61 Vulnerable Subjec ts
p.000012: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
p.000012: expectation, whether justified or not, of benefits associated with participation, or of a
p.000012: retaliatory response from senior members of a hierarchy in case of refusal to participate.
p.000012: Examples are members of a group with a hierarchical structure, such as medical, p harmacy, dental, and
p.000012: nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
p.000012: industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
p.000012: include patients with in curable diseases, persons in nur s i n g homes, unemployed or
p.000012: impoverished persons, patients in emergency situations, ethnic minority groups, homeless
p.000012: persons, nomads, refugees, minors, and those incapable of giving consent.
p.000012:
p.000012: 1.62 Well-being ( of the trial subjects)
p.000012: The physical and mental integrity of the subjects participating in a clinical trial.
p.000012:
p.000012:
p.000012:
p.000012: 2. THE PRINCIPLES OF ICH GCP
p.000012: 2.1 Clinical trials should be conducted in accordance with the ethical principles that
p.000012: have their origin in the Declaration of Helsinki, and that are consistent with GCP and the
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
p.000012: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000012: considerations and should prevail over interests of science and society.
p.000012: 2.4 The available nonclinical and clinical information on an investigational product
p.000012: should be adequate to support the proposed clinical trial.
p.000012:
p.000012:
p.000013: 13
p.000013:
p.000013: ■ 3CC1a _____________________________________________________________
p.000013:
p.000013:
p.000013:
...
Social / Trade Union Membership
Searching for indicator union:
(return to top)
p.000003: Good Clinica l Pr actice for Tri a ls on Med icin a l Prod ucts in the Europea n Co mm unity
p.000003: (III/3976/88), adopted May 1990.
p.000003:
p.000003:
p.000003: CONTENTS
p.000003:
p.000003:
p.000003: INTRODUCTION
p.000003: 1. GLOSSARY
p.000003:
p.000003: 2. THE P RINCIPLES OF ICH GCP
p.000003:
p.000003: 3. INSTITUTIONAL REVIEW BOARD / INDE P ENDENT ETHICS COMMITTEE (I RB/ I E C)
p.000003:
p.000003: 4. INVESTIGATOR
p.000003:
p.000003: 5. S P ONSOR
p.000003:
p.000003: 6. CLINICAL TRIAL P ROTOCOL AND P ROTOCOL AMENDMENT( S)
p.000003:
p.000003: 7. INVESTIGATOR’S BROCHURE
p.000003:
p.000003: 8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
p.000003:
p.000003:
p.000003: 3
p.000003:
p.000003: _____________________________________________________________ 3CC1a ■
p.000003:
p.000003:
p.000003:
p.000003: GOOD CLINICAL PRACTICE*)
p.000003:
p.000003:
p.000003:
p.000003: INTRODUCTION
p.000003: Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing,
p.000003: conducting, recording and reporting trials that involve the participation of human subjects.
p.000003: Compliance with this standard provides public assurance that the rights, safety and well-being of
p.000003: trial subjects are protected, consistent with the principles that have their origin in the Declaration
p.000003: of Helsinki, and that the clinical trial data are credible.
p.000003: The objective of this ICH GCP Guideline is to pr ovide a unified standard for the European Union
p.000003: (EU), J apan and the United States to facilitate the mutual acceptance of clinical data by the
p.000003: regulatory authorities in these jurisdictions.
p.000003: The guideline was developed with consideration of the current good clinical practices of the European
p.000003: Union, J apan, and the United States, as well as those of Australia, Canada, the Nordic countries
p.000003: and the World Health Organisation (WHO).
p.000003: This guideline should be followed when generating clinical trial data that are intended to be submitted
p.000003: to regulatory authorities.
p.000003: The principles established in this guideline may also be applied to other cli n
p.000003: ic a l investigations that may have an impact on the safety and well-being of human subjects.
p.000003:
p.000003:
p.000003: 1. GLOSSARY
p.000003: 1.1 Adverse Drug Reaction (ADR)
p.000003: In the pre-approval clinical experience with a new medicinal product or its new us ages,
p.000003: particularly as the therapeutic dose(s) may not be established: all noxious and uninten ded
p.000003: responses to a medicinal product related to any dose should be considered adverse d rug
p.000003: reactions. The phrase responses to a medicinal product means that a causal relationship between
p.000003: a medicinal product and an adverse event is at least a reasonable possibility, i.e. the
p.000003: relationship cannot be ruled out.
p.000003: Regarding marketed medicinal products: a response to a drug which is noxious a nd
p.000003: unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of
p.000003: diseases or for modif ication of physiological function (see note for guidance o n Clinical Safety
p.000003: Data Management: Definitions and Standards for Expedited Reporting ).
p.000003:
...
Social / Unemployment
Searching for indicator unemployed:
(return to top)
p.000012:
p.000012: 1.59 Trial Site
p.000012: The location(s) where trial-related activities are actually conducted.
p.000012:
p.000012:
p.000012: 1.60 Unexpected Adverse Drug Reaction
p.000012: An adverse reaction, the nature or severity of which is not consistent with the applicable
p.000012: product information (e.g., Investigator's Brochure for an unapproved investigational product or package
p.000012: insert/summary of product characteristics for an a pproved product) (see note for guidance on Clinical
p.000012: Safety Data Management: Definitions and Standards for Expedited Reporting ).
p.000012:
p.000012: 1.61 Vulnerable Subjec ts
p.000012: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
p.000012: expectation, whether justified or not, of benefits associated with participation, or of a
p.000012: retaliatory response from senior members of a hierarchy in case of refusal to participate.
p.000012: Examples are members of a group with a hierarchical structure, such as medical, p harmacy, dental, and
p.000012: nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
p.000012: industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
p.000012: include patients with in curable diseases, persons in nur s i n g homes, unemployed or
p.000012: impoverished persons, patients in emergency situations, ethnic minority groups, homeless
p.000012: persons, nomads, refugees, minors, and those incapable of giving consent.
p.000012:
p.000012: 1.62 Well-being ( of the trial subjects)
p.000012: The physical and mental integrity of the subjects participating in a clinical trial.
p.000012:
p.000012:
p.000012:
p.000012: 2. THE PRINCIPLES OF ICH GCP
p.000012: 2.1 Clinical trials should be conducted in accordance with the ethical principles that
p.000012: have their origin in the Declaration of Helsinki, and that are consistent with GCP and the
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
p.000012: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000012: considerations and should prevail over interests of science and society.
p.000012: 2.4 The available nonclinical and clinical information on an investigational product
...
Social / Youth/Minors
Searching for indicator minor:
(return to top)
p.000015:
p.000015: ■ 3CC1a _____________________________________________________________
p.000015:
p.000015:
p.000015:
p.000015: 3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum,
p.000015: as stipulated in its written operating procedures, is present.
p.000015: 3.2.4 Only members who participate in the IRB/IEC review and discussion should
p.000015: vote/provide their opinion and/or advise.
p.000015: 3.2.5 The investigator may provide information on any aspect of the trial, but should not
p.000015: participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
p.000015: 3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
p.000015:
p.000015:
p.000015: 3.3 P rocedur es
p.000015: The IRB/IEC should establish, document in writing, and follow its procedures, which should i nclu de:
p.000015: 3.3.1 Determining its composition (names and qualifications of the members) and the authority
p.000015: under which it is established.
p.000015: 3.3.2 Scheduling, notifying i t s members of, and conducting i t s meetings.
p.000015: 3.3.3 Conducting initial and continuing review of trials.
p.000015: 3.3.4 De termining the frequency of continuing review, as appropriate.
p.000015: 3.3.5 Providing, according to the applicable regulatory requirements, expedited review and
p.000015: approval/favourable opinion of minor change(s) in ongoing trials that have the
p.000015: approval/favourable opinion of the IRB/IEC.
p.000015: 3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its
p.000015: written approval/favourable opinion of the trial.
p.000015: 3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated
p.000015: without prior written IRB/IEC approval/favourable opinion of an appropriate am e n d m e nt, except
p.000015: when necessary to eliminate immediate hazards to the subjects or when the chan ge( s) involves only
p.000015: logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s))
p.000015: (see 4.5.2).
p.000015: 3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
p.000015: a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial
p.000015: subjects (see 3.3.7, 4.5.2, 4.5.4).
p.000015: b) Changes increasing the r isk to subjects and/or affecting significantly the conduct
p.000015: of the trial (see 4.10.2).
p.000015: c ) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000015: d) New information that may affect adversely the safety of the subjects or the
p.000015: conduct of the trial.
p.000015: 3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution conce rn
p.000015: i n g:
...
Social / education
Searching for indicator education:
(return to top)
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
p.000012: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000012: considerations and should prevail over interests of science and society.
p.000012: 2.4 The available nonclinical and clinical information on an investigational product
p.000012: should be adequate to support the proposed clinical trial.
p.000012:
p.000012:
p.000013: 13
p.000013:
p.000013: ■ 3CC1a _____________________________________________________________
p.000013:
p.000013:
p.000013:
p.000013: 2.5 Clinical trials should be scientifically sound, and described in a clear,
p.000013: detailed protocol.
p.000013: 2.6 A trial should be conducted in compliance with the protocol that has received prior
p.000013: institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion.
p.000013: 2.7 The medical care given to, and medical decisions made on behalf of, subjects should always
p.000013: be the responsibility of a qualified physician or, when appropriate, of a q ua lified dentist.
p.000013: 2.8 Each individual involved in conducting a trial should be qualified by education,
p.000013: training, and experience to perform his or her respective task(s).
p.000013: 2.9 Freely given informed consent should be obtained from every subject prior to clinical trial
p.000013: participation.
p.000013: 2.10 All clinical trial information should be recorded, handled, and stored in a way that
p.000013: allows its accurate reporting, interpretation and verification.
p.000013: 2.11 The confidentiality of records that could identify subjects should be protected,
p.000013: respecting the privacy and confidentiality rules in accordance with the applicable regulatory
p.000013: requirement(s).
p.000013: 2.12 Investigational products should be manufactured, handled, and stored in accor d ance with
p.000013: applicable good manufacturing practice (GMP). They should be used in accordance with the approved
p.000013: protocol.
p.000013: 2.13 Systems with procedures that assure the quality of every aspect of the trial should be im
p.000013: plemented.
p.000013:
p.000013:
p.000013: 3. INSTITUTIONAL REVIEW BOARD/INDE P ENDENT ETHICS COMMITTEE (IRB/IEC)
p.000013: 3.1 R espons ibiliti es
p.000013: 3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special
p.000013: attention should be paid to trials that may include vulnerable subjects.
p.000013: 3.1.2 The IRB/IEC should obtain the following documents:
...
p.000015: of the trial (see 4.10.2).
p.000015: c ) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000015: d) New information that may affect adversely the safety of the subjects or the
p.000015: conduct of the trial.
p.000015: 3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution conce rn
p.000015: i n g:
p.000015: a) I t s trial-related decisions/opinions.
p.000015: b) The reasons for i t s decisions/opinions.
p.000015: c ) Procedures for appeal of i t s decisions/opinions.
p.000015:
p.000015:
p.000015:
p.000016: 16
p.000016:
p.000016: _____________________________________________________________ 3CC1a ■
p.000016:
p.000016:
p.000016:
p.000016: 3.4 R eco rds
p.000016: The IRB/IEC should retain all relevant records (e.g., written procedures, membership li s t s, lis t s
p.000016: of occupations/affiliations of members, submitted documents, minutes of meetings, a nd correspondence) for
p.000016: a period of at least 3 years after completion of the trial and make them available upon request
p.000016: from the regulatory authority(ies).
p.000016: The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written
p.000016: procedures and membership lis t s.
p.000016:
p.000016:
p.000016: 4. INVESTIGATOR
p.000016: 4.1 Inves tigator’s Qualifications and Agreemen ts
p.000016: 4.1.1 The investigator(s) should be qualified by education, training, and experience to
p.000016: assume responsibility for the proper conduct of the trial, should meet all the q ualification s
p.000016: specified by the applicable regulatory requirement(s), and should provide evidence of such
p.000016: qualifications through up-to-date curriculum vitae and/or other relevant documentation requested
p.000016: by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).
p.000016: 4.1.2 The investigator should be thoroughly familiar with the appropriate use of the
p.000016: investigational product(s), as described in the protocol, in the current I nves tigator' s
p.000016: Brochure, in the product information and in other information sources provided by the
p.000016: sponsor.
p.000016: 4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable regulatory
p.000016: requirements.
p.000016: 4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and
p.000016: inspection by the appropriate regulatory authority(ies).
p.000016: 4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the
p.000016: investigator has delegated significant trial-related duties.
p.000016:
p.000016: 4.2 Adequate R esources
p.000016: 4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective data) a
p.000016: potential for recruiting the required number of suitable subjects within the agreed
p.000016: recruitment period.
...
Social / embryo
Searching for indicator embryo:
(return to top)
p.000019: information in the consent form and any other written information was accurately
p.000019: explained to, and apparently understood by, the subject or the subject's legally acceptable
p.000019: representative, and that informed consent was freely given by the subject or the subject’s
p.000019: legally acceptable representative.
p.000019: 4.8.10 Both the informed consent discussion and the written informed consent form a nd any
p.000019: other written information to be provided to subjects should include explanations of the followi n g:
p.000019:
p.000020: 20
p.000020:
p.000020: _____________________________________________________________ 3CC1a ■
p.000020:
p.000020:
p.000020:
p.000020: a) That the trial involves research.
p.000020: b) The purpose of the trial.
p.000020: c ) The trial treatment(s) and the probability for random assignment to each treatment. d) The
p.000020: trial procedures to be followed, including all invasive procedures.
p.000020: e) The subject's responsibilities.
p.000020: f ) Those aspects of the trial that are experimental.
p.000020: g ) The reasonably foreseeable r isks or inconveniences to the subject and, when
p.000020: applicable, to an embryo, foetus, or nursing infant.
p.000020: h) The reasonably expected benefits. When there is no intended clinical benefit to the
p.000020: subject, the subject should be made aware of this.
p.000020: i ) The alternative procedure(s) or course(s) of treatment that may be available to the
p.000020: subject, and their important potential benefits and risks.
p.000020: j ) The compensation and/or treatment available to the subject in the event of trial-related i n j
p.000020: ur y.
p.000020: k ) The anticipated prorated payment, if any, to the subject for participating in the trial. l )
p.000020: The anticipated expenses, if any, to the subject for participating in the trial.
p.000020: m ) That the subject's participation in the trial is voluntary and that the subject may refuse
p.000020: to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which
p.000020: the subject is otherwise entitled.
p.000020: n ) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be
p.000020: granted direct access to the subject's original medical records for verification of clinical
p.000020: trial procedures and /or data, without violating the confidentiality of the subject, to the
p.000020: extent permitted by the applicable laws and regulations and that, by signing a written informed
...
Social / employees
Searching for indicator employees:
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p.000012: 1.58 Subject Identification Code
p.000012: A unique identifier assigned by the investigator to each trial subject to protect the s ubject's
p.000012: identity and used in lieu of the subject's name when the investigator reports adverse events and/or
p.000012: other trial related data.
p.000012:
p.000012: 1.59 Trial Site
p.000012: The location(s) where trial-related activities are actually conducted.
p.000012:
p.000012:
p.000012: 1.60 Unexpected Adverse Drug Reaction
p.000012: An adverse reaction, the nature or severity of which is not consistent with the applicable
p.000012: product information (e.g., Investigator's Brochure for an unapproved investigational product or package
p.000012: insert/summary of product characteristics for an a pproved product) (see note for guidance on Clinical
p.000012: Safety Data Management: Definitions and Standards for Expedited Reporting ).
p.000012:
p.000012: 1.61 Vulnerable Subjec ts
p.000012: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
p.000012: expectation, whether justified or not, of benefits associated with participation, or of a
p.000012: retaliatory response from senior members of a hierarchy in case of refusal to participate.
p.000012: Examples are members of a group with a hierarchical structure, such as medical, p harmacy, dental, and
p.000012: nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
p.000012: industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
p.000012: include patients with in curable diseases, persons in nur s i n g homes, unemployed or
p.000012: impoverished persons, patients in emergency situations, ethnic minority groups, homeless
p.000012: persons, nomads, refugees, minors, and those incapable of giving consent.
p.000012:
p.000012: 1.62 Well-being ( of the trial subjects)
p.000012: The physical and mental integrity of the subjects participating in a clinical trial.
p.000012:
p.000012:
p.000012:
p.000012: 2. THE PRINCIPLES OF ICH GCP
p.000012: 2.1 Clinical trials should be conducted in accordance with the ethical principles that
p.000012: have their origin in the Declaration of Helsinki, and that are consistent with GCP and the
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
...
Social / gender
Searching for indicator gender:
(return to top)
p.000040: – Repeated dose
p.000040: – C arcinogenicity
p.000040: – Special studies (e.g. irritancy and sensitisation)
p.000040: – Reproductive toxicity
p.000040: – Genotoxicity (mutagenicity)
p.000040:
p.000040: 7.3.6 Effects in Hu ma ns
p.000040: Introduction:
p.000040: A thorough discussion of the known effects of the investigational product(s) in human s should
p.000040: be provided, including information on pharmacokinetics, metabolis m,
p.000040: pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where
p.000040: possible, a summary of each completed clinical trial should be provided. I nformation should also be
p.000040: provided regarding results of any use of the investigational product(s) other than from in clinical
p.000040: trials, such as from experience during marketing.
p.000040:
p.000040:
p.000041: 41
p.000041:
p.000041: ■ 3CC1a _____________________________________________________________
p.000041:
p.000041:
p.000041:
p.000041: a) Pharmacokinetics and Product Metabolism in Humans
p.000041: – A summary of information on the pharmacokinetics of the inves tigational product(s)
p.000041: should be presented, including the following, if available:
p.000041: – Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma
p.000041: protein binding, distribution, and elimination).
p.000041: – Bioavailability of the investigational product (absolute, where possible, and/or relative)
p.000041: using a reference dosage form.
p.000041: – Population subgroups (e.g., gender, age, and impaired organ function).
p.000041: – Interactions (e.g., product-product interactions and effects of food).
p.000041: – Other pharmacokinetic data (e.g., results of population studies performed within clinical
p.000041: trial(s).
p.000041: b) Safety and Efficacy
p.000041: A summary of information should be provided about the inves tigational
p.000041: product’s/products’ (inclu ding metabolites, where appropriate) safety, pharmaco- dynamics,
p.000041: efficacy, and dose response that were obtained from preceding trials i n humans (healthy
p.000041: volunteers and/or patients). The implications of this i nformat ion should be discussed. In cases
p.000041: where a number of clinical trials have been completed, the use of summaries of safety and
p.000041: efficacy across multiple trials by indications i n subgroups may provide a clear presentation of the
p.000041: data. Tabular summaries of a dver se drug reactions for all the clinical trials (inclu
p.000041: ding those for all the studied indications) would be useful. Important differences
p.000041: in adverse drug reaction patterns/incidences across indications or subgroups should be discussed.
p.000041: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
(return to top)
p.000007: Data
p.000007: Monitoring Committee)
p.000007: An independent data-monitoring committee that may be established by the sponsor to assess at intervals
p.000007: the progress of a clinical trial, the safety data, and the critical efficacy endpoints,
p.000007: and to recommend to the sponsor whether to continue, modify, or stop a trial.
p.000007:
p.000007: 1.26 Impartial Wit ness
p.000007: A person, who is independent of the trial, who cannot be unfairly influenced by people
p.000007: involved with the trial, who attends the informed consent process if the subject or the
p.000007: subject’s legally acceptable representative cannot read, and who reads the informed consent form and
p.000007: any other written information supplied to the subject.
p.000007:
p.000007: 1.27 Independent Ethics Committee (IEC)
p.000007: An independent body (a review board or a committee, institutional, regional, national, or
p.000007: supranational), constituted of medical professionals and non-medical members, whose
p.000007: responsibility it is to ensure the protection of the rights, safety and well-being of human
p.000007: subjects involved in a trial and to pro vide public assurance of that protection, by, am o n g
p.000007: other things, reviewing and approving / providing favourable opinion on, the trial protocol,
p.000007:
p.000008: 8
p.000008:
p.000008: _____________________________________________________________ 3CC1a ■
p.000008:
p.000008:
p.000008:
p.000008: the suitabi lity of the investigator(s), facilities, and the methods and material to be used i n
p.000008: obtaining and documenting informed consent of the trial subjects.
p.000008: The legal status, composition, function, operations and regulatory requirements pe rtaining to
p.000008: Independent Ethics Committees may differ among countries, but should allow the
p.000008: Independent Ethics Committee to act in agreement with GCP as described in this guideline.
p.000008:
p.000008: 1.28 Informed Consent
p.000008: A process by which a subject voluntarily confirms his or her willingness to participate in a
p.000008: particular trial, after having been informed of all aspects of the trial that are relevant to the
p.000008: subject's decision to participate. Informed consent is documented by means of a written, signed
p.000008: and dated informed consent form.
p.000008:
p.000008: 1.29 Inspec tio n
p.000008: The act by a regul atory authority(ies) of conducting an official review of documents,
...
p.000009: applicable regulatory requirements”.
p.000009:
p.000009: 1.36 Investigator’s Brochure
p.000009: A compilation of the clinical and nonclinical data on the investigational product(s) which i s relevant
p.000009: to the study of the investigational product(s) in human subjects (see 7. Investigator’s Brochure).
p.000009:
p.000009: 1.37 Legally Acceptable Representative
p.000009: An individual or juridical or other body authorised under applicable law to consent, o n behalf
p.000009: of a prospective subject, to the subject’s participation in the clinical trial.
p.000009:
p.000009: 1.38 Monito ri ng
p.000009: The act of overseeing the progress of a clinical trial, and of ensuring that it is con ducted,
p.000009: recorded, and reported in acc ordance with the protocol, Standard Operating Procedures (SOPs),
p.000009: Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
p.000009:
p.000009: 1.39 Monitoring Report
p.000009: A written report from the monitor to the sponsor after each site visit and/or other trial-related
p.000009: communication according to the sponsor’s SOPs.
p.000009:
p.000009: 1.40 Multicentre Trial
p.000009: A clinical trial conducted according to a single protocol but at more than one site, a nd
p.000009: therefore, carried out by more than one investigator.
p.000009:
p.000009: 1.41 Noncli n ical Study
p.000009: Biomedical studies not performed on human subjects.
p.000009:
p.000009:
p.000009: 1.42 Opinion ( in relation to Independent Ethics Committee)
p.000009: The judgement and/or the advice provided by an Independent Ethics Committee (IEC).
p.000009:
p.000009:
p.000009: 1.43 Origi nal Med ical R ecord
p.000009: See Source Documents.
p.000009:
p.000009:
p.000010: 10
p.000010:
p.000010: _____________________________________________________________ 3CC1a ■
p.000010:
p.000010:
p.000010:
p.000010: 1.44 P r otoco l
p.000010: A document that describes the object ive(s), design, methodology, statistical consi de ration s, and
p.000010: organisation of a trial. The protocol usually also gives the background and rationale for the trial, but
p.000010: these could be provided in other protocol referenced documents. Throughout the GCP Guideline the term
p.000010: protocol refers to protocol and protocol amendments.
p.000010:
p.000010: 1.45 P rotocol Amendmen t
p.000010: A written description of a change(s) to or formal clarification of a protocol.
p.000010:
p.000010:
p.000010: 1.46 Quality Assurance (QA)
p.000010: All those planned and systematic actions that are established to ensure that the trial i s
p.000010: performed and the data are generated, documented (recorded), and reported in com pli ance with Good
p.000010: Clinical Practice (GCP) and the applicable regulatory requirement(s).
p.000010:
p.000010: 1.47 Quality Control (QC)
p.000010: The operational techniques and activities undertaken within the quality assurance system to verify that
p.000010: the requirements for quality of the trial-related activities have been fulfilled.
p.000010:
p.000010: 1.48 Ra ndom isatio n
...
p.000012: The physical and mental integrity of the subjects participating in a clinical trial.
p.000012:
p.000012:
p.000012:
p.000012: 2. THE PRINCIPLES OF ICH GCP
p.000012: 2.1 Clinical trials should be conducted in accordance with the ethical principles that
p.000012: have their origin in the Declaration of Helsinki, and that are consistent with GCP and the
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
p.000012: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000012: considerations and should prevail over interests of science and society.
p.000012: 2.4 The available nonclinical and clinical information on an investigational product
p.000012: should be adequate to support the proposed clinical trial.
p.000012:
p.000012:
p.000013: 13
p.000013:
p.000013: ■ 3CC1a _____________________________________________________________
p.000013:
p.000013:
p.000013:
p.000013: 2.5 Clinical trials should be scientifically sound, and described in a clear,
p.000013: detailed protocol.
p.000013: 2.6 A trial should be conducted in compliance with the protocol that has received prior
p.000013: institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion.
p.000013: 2.7 The medical care given to, and medical decisions made on behalf of, subjects should always
p.000013: be the responsibility of a qualified physician or, when appropriate, of a q ua lified dentist.
p.000013: 2.8 Each individual involved in conducting a trial should be qualified by education,
p.000013: training, and experience to perform his or her respective task(s).
p.000013: 2.9 Freely given informed consent should be obtained from every subject prior to clinical trial
p.000013: participation.
p.000013: 2.10 All clinical trial information should be recorded, handled, and stored in a way that
p.000013: allows its accurate reporting, interpretation and verification.
p.000013: 2.11 The confidentiality of records that could identify subjects should be protected,
p.000013: respecting the privacy and confidentiality rules in accordance with the applicable regulatory
p.000013: requirement(s).
p.000013: 2.12 Investigational products should be manufactured, handled, and stored in accor d ance with
p.000013: applicable good manufacturing practice (GMP). They should be used in accordance with the approved
p.000013: protocol.
p.000013: 2.13 Systems with procedures that assure the quality of every aspect of the trial should be im
p.000013: plemented.
p.000013:
p.000013:
p.000013: 3. INSTITUTIONAL REVIEW BOARD/INDE P ENDENT ETHICS COMMITTEE (IRB/IEC)
p.000013: 3.1 R espons ibiliti es
p.000013: 3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special
p.000013: attention should be paid to trials that may include vulnerable subjects.
p.000013: 3.1.2 The IRB/IEC should obtain the following documents:
p.000013: trial protocol(s)/amendment(s), written informed consent form(s) and consent fo rm updates that
p.000013: the investigator proposes for use in the trial, subject rec ruitment procedures (e.g.
p.000013: advertisements), written information to be provided to subjects, Investigator's Brochure (IB),
p.000013: available safety information, information about payments and compensation available
p.000013: to subjects, the investigator’s current curriculum vitae and/or other documentation evidencing
p.000013: qualifications, and any other documents that the IRB/IEC may need to fulfil its responsibilities.
p.000013: The IRB/IEC should review a proposed clinical trial within a reasonable time a nd document its
p.000013: views in writing, clearly identifying the trial, the documents reviewed and the dates for the
p.000013: following:
p.000013: • approval/favourable opinion;
p.000013: • modifications required prior to i t s approval/favourable opinion;
p.000013:
p.000013:
p.000014: 14
p.000014:
p.000014: _____________________________________________________________ 3CC1a ■
p.000014:
p.000014:
p.000014:
p.000014: • disapproval/negative opinion; and
p.000014: • termination/suspension of any prior approval/favourable opinion.
p.000014: 3.1.3 The IRB/IEC should consider the qualifications of the investigator for the proposed trial,
p.000014: as documented by a current curriculum vitae and/or by any other relevant
p.000014: documentation the IRB/IEC requests.
p.000014: 3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at int e rvals
p.000014: appropriate to the degree of risk to human subjects, but at least once per year.
p.000014: 3.1.5 The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given
p.000014: to subjects when, in the judgement of the IRB/IEC, the additional information would add meaningfully
p.000014: to the protection of the rights, safety and/or well-being of the subjects.
p.000014: 3.1.6 When a non-therapeutic trial is to be carried out with the consent of the subject’s
p.000014: legally acceptable representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed
p.000014: protocol and /or other document(s) adequately addresses relevant ethical conce rn s and meets
p.000014: applicable regulatory requirements for such trials.
p.000014: 3.1.7 Where the protocol indicates that prior consent of the trial subject or the subject’s
p.000014: legally acceptable representative is not possible (see 4. 8.15), the IRB/IEC should de t ermine that
p.000014: the proposed protocol and /or other document(s) adequately addresses relevant ethical concerns and
...
p.000014: 3.1.8 The IRB/IEC should review both the amount and method of payment to subjects to assure
p.000014: that neither presents problems of coercion or undue influence on the trial subjects. Payments to
p.000014: a subject should be prorated and not wholly contingent on completion of the tr i a l by the subject.
p.000014: 3.1.9 The IRB/IEC should ensure that information regarding payment to subjects,
p.000014: including the methods, amounts, and schedule of payment to trial subjects, is set forth in the
p.000014: written informed consent form and any other written information to be provided to subjects. The way
p.000014: payment will be prorated should be specified.
p.000014:
p.000014: 3.2 Composition, Functions and Operations
p.000014: 3.2.1 The IRB/IEC should consist of a reasonable number of members, who collectively have the
p.000014: qualifications and experience to review and evaluate the science, medical aspects, and ethics of the
p.000014: proposed trial. I t is recommended that the IRB/IEC should include:
p.000014: a) At least five members.
p.000014: b) At least one member whose primary area of interest is in a nonscientific area. c ) At
p.000014: least one member who is independent of the institution/trial site.
p.000014: Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial
p.000014: should vote/provide opinion on a trial-related matter.
p.000014: A lis t of IRB/IEC members and their qualifications should be maintained.
p.000014: 3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should
p.000014: maintain written records of its activities and minutes of its meetings, and should comply with
p.000014: GCP and with the applicable regulatory requirement(s).
p.000014:
p.000014:
p.000014:
p.000015: 15
p.000015:
p.000015: ■ 3CC1a _____________________________________________________________
p.000015:
p.000015:
p.000015:
p.000015: 3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum,
p.000015: as stipulated in its written operating procedures, is present.
p.000015: 3.2.4 Only members who participate in the IRB/IEC review and discussion should
p.000015: vote/provide their opinion and/or advise.
p.000015: 3.2.5 The investigator may provide information on any aspect of the trial, but should not
p.000015: participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
p.000015: 3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
p.000015:
p.000015:
p.000015: 3.3 P rocedur es
p.000015: The IRB/IEC should establish, document in writing, and follow its procedures, which should i nclu de:
p.000015: 3.3.1 Determining its composition (names and qualifications of the members) and the authority
p.000015: under which it is established.
p.000015: 3.3.2 Scheduling, notifying i t s members of, and conducting i t s meetings.
p.000015: 3.3.3 Conducting initial and continuing review of trials.
p.000015: 3.3.4 De termining the frequency of continuing review, as appropriate.
p.000015: 3.3.5 Providing, according to the applicable regulatory requirements, expedited review and
p.000015: approval/favourable opinion of minor change(s) in ongoing trials that have the
p.000015: approval/favourable opinion of the IRB/IEC.
p.000015: 3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its
p.000015: written approval/favourable opinion of the trial.
p.000015: 3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated
p.000015: without prior written IRB/IEC approval/favourable opinion of an appropriate am e n d m e nt, except
p.000015: when necessary to eliminate immediate hazards to the subjects or when the chan ge( s) involves only
p.000015: logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s))
p.000015: (see 4.5.2).
p.000015: 3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
p.000015: a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial
p.000015: subjects (see 3.3.7, 4.5.2, 4.5.4).
p.000015: b) Changes increasing the r isk to subjects and/or affecting significantly the conduct
p.000015: of the trial (see 4.10.2).
p.000015: c ) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000015: d) New information that may affect adversely the safety of the subjects or the
p.000015: conduct of the trial.
p.000015: 3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution conce rn
p.000015: i n g:
p.000015: a) I t s trial-related decisions/opinions.
p.000015: b) The reasons for i t s decisions/opinions.
p.000015: c ) Procedures for appeal of i t s decisions/opinions.
p.000015:
p.000015:
p.000015:
p.000016: 16
p.000016:
p.000016: _____________________________________________________________ 3CC1a ■
p.000016:
p.000016:
p.000016:
p.000016: 3.4 R eco rds
p.000016: The IRB/IEC should retain all relevant records (e.g., written procedures, membership li s t s, lis t s
p.000016: of occupations/affiliations of members, submitted documents, minutes of meetings, a nd correspondence) for
...
p.000017:
p.000017:
p.000017:
p.000017: 4.3 Medical Care of Trial Subjects
p.000017: 4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub-
p.000017: investigator for the trial, should be responsible for all trial-related medical (or de ntal)
p.000017: decision s .
p.000017: 4.3.2 During and following a subject’s participation in a trial, the investigator/institution should
p.000017: ensure that a dequate medical care is provided to a subject for any adverse events, inclu ding
p.000017: clinically significant laboratory values, related to the trial. The
p.000017: investigator/institution should inform a subject when medical care is needed for
p.000017: intercurrent illness(es) of which the investigator becomes aware.
p.000017: 4.3.3 It is recommended that the investigator inform the subject's primary physician about the
p.000017: subject's participation in the trial if the subject has a primary physician and if the
p.000017: subject agrees to the primary physician being informed.
p.000017: 4.3.4 Although a subject is not obliged to give his/her reason(s) for with d
p.000017: rawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the
p.000017: reason(s), while fully respecting the subject’s rights.
p.000017:
p.000017: 4.4 Communication w it h IRB/IEC
p.000017: 4.4.1 Before initiating a trial, the investigator/institution should have written and dated
p.000017: approval/favourable opinion from the IRB/IEC for the trial protocol, written i nform ed
p.000017: consent form, consent form updates, subject recruitment procedures (e.g., advertisements), and any
p.000017: other written information to be provided to subjects.
p.000017: 4.4.2 As part of the investigator’s/institution’s written application to the IRB/IEC, the
p.000017: investigator/institution should provide the IRB/IEC with a current copy of the I nves tigator' s Brochure.
p.000017: If the Investigator's Brochure is updated during the trial, the
p.000017: investigator/institution should supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
p.000017: 4.4.3 During the trial the investigator/institution should provide to the IRB/IEC a l l
p.000017: documents subject to review.
p.000017:
p.000017: 4.5 Compliance w it h P rotocol
p.000017: 4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed
p.000017: to by the sponsor and, if required, by the regul atory authority(ies) and which was given
p.000017: approval/favourable opinion by the IRB/IEC. The investigator/institution and the sponsor should
p.000017: sign the protocol, or an alternative contract, to confirm agreement.
p.000017: 4.5.2 The investigator should not implement any deviation from, or changes of the protocol without
p.000017: agreement by the sponsor and prior review and documented approval/favourable opinion from the
p.000017: IRB/IEC of an amendment, except where necessary to eliminate a n immediate hazard(s) to
p.000017: trial su bjects, or when the change(s) involves only logistical or administrative aspects of
p.000017: the trial (e.g., change in monitor(s), change of telephone num be r(s)).
p.000017: 4.5.3 The investigator, or person designated by the investigator, should document a nd
p.000017: explain any deviation from the approved protocol.
p.000017: 4.5.4 The investigator may implement a deviation from, or a change of, the protocol to
p.000017: eliminate an immediate hazard(s) to trial subjects without prior
p.000017: IRB/IEC
p.000017:
p.000018: 18
p.000018:
p.000018: _____________________________________________________________ 3CC1a ■
p.000018:
p.000018:
p.000018:
p.000018: approval/favourable opinion. As soon as possible, the i mplemented deviation or change, the reasons
p.000018: for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:
p.000018: a) to the IRB/IEC for review and approval/favourable opinion,
p.000018: b) to the sponsor for agreement and, if required, c ) to the regulatory authority(ies).
p.000018:
p.000018: 4.6 Inves tigatio nal P roduct( s)
p.000018: 4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests
p.000018: with the investigator/institution.
p.000018: 4.6.2 Where allowed/required, the investigator/institution may/should assign some or a l l of the
p.000018: investigator’s/institution’s duties for investigational product(s) accountability at the trial site(s)
p.000018: to an appropriate pharmacist or another appropriate individual who is under the supervision of the
p.000018: investigator/institution.
p.000018: 4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who
p.000018: is designated by the investigator/institution, should maintain records of the product's
p.000018: delivery to the trial site, the inventory at the site, the use by each subject, and the return to
p.000018: the
p.000018: sponsor or alternative disposition of unused product(s). These records should include dates, quantities,
p.000018: batch/serial numbers, expiration dates (if applicable), and the unique code numbers
p.000018: assigned to the investigational product(s) and trial subjects. Investigators should maintain records
p.000018: that document adequately that the subjects were provided the doses specified by the
p.000018: protocol and reconcile all investigational product(s) received from the sponsor.
p.000018: 4.6.4 The investigational product(s) should be s tored as specified by the sponsor (see 5.13.2 and
p.000018: 5.14.3) and in accordance with applicable regulatory requirement(s).
p.000018: 4.6.5 The investigator should ensure that the investigational product(s) are used only i n
p.000018: accordance with the approved protocol.
p.000018: 4.6.6 The investigator, or a person designated by the investigator/institution, should
p.000018: explain the correct use of the investigational product(s) to each subject and should check, at
p.000018: intervals appropriate for the trial, that each subject is following the instructions properly.
p.000018:
p.000018: 4.7 Ra ndom isatio n P rocedures and Unblind i ng
p.000018: The investigator should follow the trial’s randomisation procedures, if any, and should ensure
p.000018: that the code is broken only in accordance with the protocol. If the trial is blinded, the
p.000018: investigator should promptly document and explain to the sponsor any premature
p.000018: unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the
p.000018: investigational product(s).
p.000018:
p.000018: 4.8 Informed Consent of Trial Subjects
p.000018: 4.8.1 In obtaining and documenting informed consent, the investigator should com ply with
p.000018: the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that
p.000018: have their origin in the Declaration of Helsinki. Prior to the beginning of the
p.000018: trial, the investigator should have the IRB/IEC's written approval/favourable opinion of the written
p.000018: informed consent form and any other written information to be provided to subjects.
p.000018:
p.000019: 19
p.000019:
p.000019: ■ 3CC1a _____________________________________________________________
p.000019:
p.000019:
p.000019:
p.000019: 4.8.2 The written informed consent form and any other written information to be provided to
p.000019: subjects should be revised whenever important new information becomes available that may be
p.000019: relevant to the subject’s consent. Any revised written informed consent form, a nd written
p.000019: information should receive the IRB/IEC's approval/favourable opinion in advance of use. The subject or the
p.000019: subject’s legally acceptable representative should be informed in a t imely manner if new
p.000019: information becomes available that may be relevant to the subject’s willingness to continue
p.000019: participation in the trial. The communication of this i nformat ion should be documented.
p.000019: 4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a
p.000019: subject to participate or to continue to participate in a trial.
p.000019: 4.8.4 None of the oral and written information concerning the trial, including the written informed
p.000019: consent form, should contain any language that causes the subject or the subject’s legally
p.000019: acceptable representative to waive or to appear to waive any legal rights, or that releases
p.000019: or appears to release the investigator, the institution, the sponsor, or their agents from
p.000019: liability or negligence.
p.000019: 4.8.5 The investigator, or a person designated by the investigator, should fully inform the
p.000019: subject or, if the subject is unable to provide informed consent, the subject’s leg a
p.000019: lly acceptable representative, of all pertinent aspects of the trial including the
p.000019: written information and the approval/favourable opinion by the IRB/IEC.
p.000019: 4.8.6 The language u sed in the oral and written information about the trial, including the
p.000019: written informed consent form, should be as non-technical as practical and should be
p.000019: understandable to the subject or the subject's legally acceptable representative and the
p.000019: impartial witness, where applicable.
p.000019: 4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the
p.000019: investigator, should provide the subject or the subject's legally acceptable representative ample time
p.000019: and opportunity to inquire about details of the trial and to decide whether or not to
p.000019: participate in the trial. All questions about the trial should be answered to the satisfaction of
p.000019: the subject or the subject's legally acceptable representative.
p.000019: 4.8.8 Prior to a subject’s participation in the trial, the written informed consent fo rm
p.000019: should be signed and personally dated by the subject or by the subject's legally acceptable
p.000019: representative, and by the person who conducted the informed consent discussion.
p.000019: 4.8.9 If a subject is unable to read or if a legally acceptable representative is unable
p.000019: to read, an impartial witness should be present during the entire informed consent discu ssion. After
...
p.000021: enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g., minors,
p.000021: or patients with severe dementia), the subject should be informed about the trial to the extent
p.000021: compatible with the subject’s understanding and, if capable, the subject should sign and personally date
p.000021: the written informed consent.
p.000021: 4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e. a trial in which there is no
p.000021: anticipated direct clinical benefit to the subject), should be conducted in subjects who
p.000021: personally give consent and who sign and date the written informed consent form.
p.000021: 4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a leg a lly
p.000021: acceptable representative provided the following conditions are fulfilled:
p.000021: a) The objectives of the trial can not be met by means of a trial in subjects who can give
p.000021: informed consent personally.
p.000021: b) The foreseeable risks to the subjects are low.
p.000021: c ) The negative impact on the subject’s well-being is minimised and low. d) The trial is not
p.000021: prohibited by law.
p.000021: e) The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such
p.000021: subjects, and the written approval/ favourable opinion covers this aspect.
p.000021: Such trials, unless an exception is justified, should be conducted in patients having a
p.000021: disease or condition for which the investigational product is intended. Subjects in these
p.000021: trials should be particularly closely monitored and should be withdrawn if they appear to be unduly
p.000021: distressed.
p.000021: 4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the
p.000021: subject's legally acceptable representative, if present, should be requested. When prior consent of
p.000021: the subject is not possible, and the subject’s legally acceptable representative is not
p.000021: available, enrolment of the subject should require measures described in the protocol and/or elsewhere,
p.000021: with documented approval/favourable opinion by the IRB/IEC, to protect the rights, safety and
p.000021: well-being of the subject and to ensure compliance with applicable regulatory requirements. The
p.000021: subject or the subject's legally acceptable representative should be informed about the trial
p.000021: as soon as possible and consent to continue and other consent as appropriate (see 4.8.10) should be
p.000021: requested.
p.000021:
p.000021: 4.9 Records and Reports
p.000021: 4.9.1 The investigator should ensure the accuracy, completeness, legibility, and t imeliness of the
p.000021: data reported to the sponsor in the CRFs and in all required reports.
p.000021: 4.9.2 Data reported on the CRF, that are derived from source documents, should be
p.000021: consistent with the source documents or the discrepancies should be explained.
p.000021: 4.9.3 Any change or correction to a CRF should be dated, initialled, and explained ( i f
p.000021: necessary) and should not obscure the original entry (i.e. an audit trail should
p.000021: be maintained); this applies to both written and electronic changes or corrections (see 5.18.4
p.000021: (n)). Sponsors should provide guidance to investigators and /or the investigators' designated
p.000021: representatives on making such corrections. Sponsors should have written procedures to
p.000021:
p.000022: 22
p.000022:
p.000022: _____________________________________________________________ 3CC1a ■
p.000022:
p.000022:
p.000022:
...
p.000022:
p.000022:
p.000022:
p.000022:
p.000023: 23
p.000023:
p.000023: ■ 3CC1a _____________________________________________________________
p.000023:
p.000023:
p.000023:
p.000023: 4.12 Premature Termination or Suspension of a Trial
p.000023: If the trial is prematurely terminated or suspended for any reason,
p.000023: the
p.000023: investigator/institution should promptly inform the trial subjects, should assure appropr iate therapy
p.000023: and follow-up for the s ubjects, and, where required by the applicable regulatory requirement(s),
p.000023: should inform the regulatory authority(ies). In addition:
p.000023: 4.12.1 If the investigator terminates or suspends a trial without prior agreement of the
p.000023: sponsor, the investigator should inform the institution where applicable, and the
p.000023: investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the
p.000023: sponsor and the IRB/IEC a detailed written explanation of the termination or suspension.
p.000023: 4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should
p.000023: promptly inform the institution where applicable and the investigator/institution should promptly
p.000023: inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or
p.000023: suspension.
p.000023: 4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see
p.000023: 3.1.2 and 3.3.9), the investigator should inform the institution where applicable and the
p.000023: investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed
p.000023: written explanation of the termination or suspension.
p.000023:
p.000023: 4.13 Final Report( s) by Investigator
p.000023: Upon completion of the trial, the investigator, where applicable, should inform the
p.000023: institution; the investigator/institution should provide the IRB/IEC with a summ ary of the trial’s
p.000023: outcome, and the regulatory authority(ies) with any reports required.
p.000023:
p.000023:
p.000023: 5. S PONSOR
p.000023: 5.1 Quality Assurance and Quality Control
p.000023: 5.1.1 The sponsor is responsible for implementing and maintaining quality a ss urance and
p.000023: quality control systems with written SOPs to ensure that trials are conducted and data are generated,
p.000023: documented (recorded), and reported in compliance with the protocol, GCP, and the applicable
p.000023: regulatory requirement(s).
p.000023: 5.1.2 The sponsor is responsible for securing agreement from all involved parties to
p.000023: ensure direct access (see 1.21) to all trial related sites, source data/documents, and reports for
p.000023: the purpose of monitoring and auditing by the sponsor, and inspection by domestic a nd foreign
p.000023: regulatory authorities.
p.000023: 5.1.3 Quality control should be applied to each stage of data handling to ensure that a l l
...
p.000025: retention and should notify the investigator(s)/institution(s) in writing when the tr i a l related
p.000025: records are no longer needed.
p.000025:
p.000025: 5.6 Investigator Selection
p.000025: 5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each
p.000025: investigator should be qualified by training and experience and should have adequate resources
p.000025: (see 4.1, 4.2) to properly conduct the trial for which the investigator is selected. If organisation
p.000025: of a co-ordinating committee and/or selection of co-ordinating inves tigator(s)
p.000025:
p.000026: 26
p.000026:
p.000026: _____________________________________________________________ 3CC1a ■
p.000026:
p.000026:
p.000026:
p.000026: are to be utilised in multicentre trials, their organisation and/or selection are the spon sor' s
p.000026: responsibility.
p.000026: 5.6.2 Before entering an agreement with an investigator/institution to conduct a trial, the sponsor
p.000026: should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator’s
p.000026: Brochure, and should provide sufficient time for the investigator/institution to review the protocol and
p.000026: the information provided.
p.000026: 5.6.3 The sponsor should obtain the investigator's/institution's agreement:
p.000026: a) to conduct the trial in compliance with GCP, with the applicable
p.000026: regulatory requirement(s) (see 4.1.3), and with the protocol agreed to by the sponsor and give n
p.000026: approval/favourable opinion by the IRB/IEC (see 4.5.1);
p.000026: b) to comply with procedures for data recording/reporting;
p.000026: c ) to permit monitoring, auditing and inspection (see 4.1.4) and
p.000026: d) to retain the trial related essential documents until the sponsor informs
p.000026: the investigator/institution these documents are no longer needed (see 4.9.4 and 5.5.12).
p.000026: The sponsor and the investigator/institution should sign the protocol, or an alternative
p.000026: document, to confirm this agreement.
p.000026:
p.000026: 5.7 Allocation of R espons ibiliti es
p.000026: Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related
p.000026: duties and functions.
p.000026:
p.000026: 5.8 Compensation to Subjects and Investigators
p.000026: 5.8.1 If required by the applicable regulatory requirement(s), the sponsor should provide
p.000026: insurance or should in de mnify (legal and financial coverage) the inves tigator/the
p.000026: institution against claims arising from the trial, except for claims that arise f r o
p.000026: m malpractice and/or negligence.
p.000026: 5.8.2 The sponsor's policies and procedures should address the costs of treatment of tr i a l
p.000026: subjects in the event of trial-related injuries in accordance with the applicable regulatory
p.000026: requirement(s).
p.000026: 5.8.3 When trial subjects receive compensation, the method and manner of compensation should comply
p.000026: with applicable regulatory requirement(s).
p.000026:
p.000026: 5.9 Financing
p.000026: The financial aspects of the trial should be documented in an agreement between the sponsor and the
p.000026: investigator/institution.
p.000026:
p.000026: 5.10 Notificatio n/Submission to R egulatory Au t hority( i es)
p.000026: Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, i f
p.000026: required by the applicable regulatory requirement(s)) should submit any required
p.000026: application(s) to the appropriate authority(ies) for review, acceptance, a nd/or permission ( as
p.000026: required by the applicable regulatory requirement(s)) to begin the trial(s). A n
p.000026: y
p.000026:
p.000026:
p.000027: 27
p.000027:
p.000027: ■ 3CC1a _____________________________________________________________
p.000027:
p.000027:
p.000027:
p.000027: notification/submission should be dated and contain sufficient information to identify the protocol.
p.000027:
p.000027: 5.11 Confirmation of Revie w by IRB/IEC
p.000027: 5.11.1 The sponsor should obtain from the investigator/institution:
p.000027: a) The name and address of the investigator's/institution’s IRB/IEC.
p.000027: b) A statement obtained from the IRB/IEC that it is organised and operates according to GCP
p.000027: and the applicable laws and regulations.
p.000027: c ) Documented IRB/IEC approval/favourable opinion and, if requested by the spons or, a current
p.000027: copy of protocol, written informed consent form(s) and any other written information to be
p.000027: provided to subjects, subject recruiting procedures, and documents related to payments and
p.000027: compensation available to the su bjects, and any other documents that the IRB/IEC may have
p.000027: requested.
p.000027: 5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s) in a ny aspect
p.000027: of the trial, such as modification(s) of the protocol, written informed consent form a nd any other
p.000027: written information to be provided to subjects, and/or other procedures, the sponsor should obtain from
p.000027: the investigator/institution a copy of the modification(s) made and the date approval/favourable
p.000027: opinion was given by the IRB/IEC.
p.000027: 5.11.3 The sponsor should obtain from the investigator/institution documentation and dates of any
p.000027: IRB/IEC reapprovals/re-evaluations with favourable opinion, and of any with drawals or suspensions of
p.000027: approval/favourable opinion.
p.000027:
p.000027: 5.12 Informa tio n on Inves tigatio nal P roduct( s)
p.000027: 5.12.1 When planning trials, the sponsor should ensure that s ufficient safety and efficacy data
p.000027: from nonclinical studies and/or clinical trials are available to support human exposure
p.000027: by the route, at the dosages, for the duration, and in the trial population to be studied.
p.000027: 5.12.2 The sponsor should update the Investigator’s Brochure as significant new
p.000027: information becomes available (see 7. Investigator's Brochure).
p.000027:
p.000027: 5.13 Manufacturing, P ackaging, Labelling, and Coding Inves tigatio nal P roduct( s)
p.000027: 5.13.1 The sponsor should ensure that the investigational product(s) (inclu ding active
p.000027: comparator(s) and placebo, if applicable) is characterised as appropriate to the stage of
p.000027: development of the product(s), is manufactured in accordance with any applicable GMP, a nd
p.000027: is coded and labelled in a manner that protects the blinding, if applicable. In addition, the
p.000027: labelling should comply with applicable regulatory requirement(s).
p.000027: 5.13.2 The sponsor should determine, for the investigational product(s), acceptable s torage
p.000027: temperatures, storage conditions (e.g. protection from light), s torage times, reconstitution fluids
p.000027: and procedures, and devices for product infusion, if any. The sponsor should i n fo rm all involved
p.000027: parties (e.g. monitors, investigators, pharmacists, s torage managers) of these de t ermination s.
p.000027: 5.13.3 The investigational product(s) should be packaged to prevent contamination a nd
p.000027: unacceptable deterioration during transport and s torage.
p.000027:
p.000028: 28
p.000028:
p.000028: _____________________________________________________________ 3CC1a ■
p.000028:
p.000028:
p.000028:
p.000028: 5.13.4 In blinded trials, the coding system for the investigational product(s) should i ncl u de a
p.000028: mechanism that permits rapid identification of the product(s) in case of a m edica l
p.000028: emergency, but does not permit undetectable breaks of the blinding.
p.000028: 5.13.5 If significant formulation changes are made in the investigational or comparator
p.000028: product(s) during the course of clinical development, the results of any additional studies of the
p.000028: formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether
p.000028: these changes would significantly alter the pharmacokinetic profile of the product should be
p.000028: available prior to the use of the new formulation in clinical trials.
p.000028:
p.000028: 5.14 Supplying and Ha ndling Inves tigatio nal P roduct( s)
p.000028: 5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the
p.000028: investigational product(s).
p.000028: 5.14.2 The sponsor should not supply an investigator/institution with the inves tigational
p.000028: product(s) until the sponsor obtains all required documentation (e.g. approval/favourable opinion
p.000028: from IRB/IEC and regulatory authority(ies)).
p.000028: 5.14.3 The sponsor should ensure that written procedures include instructions that the
p.000028: investigator/institution should follow for the handling and storage of inves tigational
p.000028: product(s) for the trial and documentation thereof. The procedures should address adequate and safe
p.000028: receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of
p.000028: unused investigational product(s) to the sponsor (or alternative disposition i f authorised by the
p.000028: sponsor and in compliance with the applicable regulatory requirement(s)).
p.000028: 5.14.4 The sponsor should:
p.000028: a) Ensure timely delivery of investigational product(s) to the investigator(s).
p.000028: b) Maintain records that document shipment, receipt, disposition, return, and destruction of the
p.000028: investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical T r i a
p.000028: l).
p.000028: c ) Maintain a system for retrieving investigational products and documenting this
p.000028: retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product
p.000028: reclaim).
p.000028: d) Maintain a system for the disposition of unused investigational product(s) and for the
p.000028: documentation of this disposition.
p.000028: 5.14.5 The sponsor should:
p.000028: a) Take steps to ensure that the investigational product(s) are stable over the period of use.
...
p.000028: retained either until the analyses of the trial data are complete or as required by the applicable
p.000028: regulatory requirement(s), whichever represents the longer retention period.
p.000028:
p.000028: 5.15 R ecord Access
p.000028: 5.15.1 The sponsor should ensure that it is specified in the protocol or other written
p.000028: agreement that the investigator(s)/institution(s) provide direct access to
p.000028: source
p.000028:
p.000028:
p.000029: 29
p.000029:
p.000029: ■ 3CC1a _____________________________________________________________
p.000029:
p.000029:
p.000029:
p.000029: data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory
p.000029: inspection.
p.000029: 5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to
p.000029: his/her original medical records for trial-related monitoring, audit, IRB/IEC review, a nd regulatory
p.000029: inspection.
p.000029:
p.000029: 5.16 Safe ty Informa tio n
p.000029: 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the inves tigational
p.000029: product(s).
p.000029: 5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) a nd the
p.000029: regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact
p.000029: the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial.
p.000029:
p.000029: 5.17 Adverse Drug Reaction Reporting
p.000029: 5.17.1 The sponsor should expedite the reporting to all
p.000029: conce rn ed investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the
p.000029: regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected.
p.000029: 5.17.2 Such expedited reports should co mply with the applicable regulatory requir ement(s) and with
p.000029: the note for guidance on Clinical Safety Data Management: Definitions and Standards for
p.000029: Expedited Reporting .
p.000029: 5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates a nd
p.000029: periodic reports, as required by applicable regulatory requirement(s).
p.000029:
p.000029: 5.18 Monito ri ng
p.000029: 5.18.1 Purpose
p.000029: The purposes of trial monitoring are to verify that:
p.000029: a) The rights and well-being of human subjects are protected.
p.000029: b) The reported trial data are accurate, complete, and verifiable from source documents.
p.000029: c ) The conduct of the trial is in compliance with the currently
p.000029: approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
p.000029:
p.000029: 5.18.2 Selection a n d Qualifica tions of Monitors
p.000029: a) Monitors should be appointed by the sponsor.
...
p.000033: If a trial is prematurely terminated or suspended, the sponsor should promptly inform the
p.000033: investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the
p.000033: reason(s) for the termination or suspension. The IRB/IEC should also be i nform ed promptly and provided
p.000033: the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as
p.000033: specified by the applicable regulatory requirement(s).
p.000033:
p.000033: 5.22 Cli n ical Trial/Study R eports
p.000033: Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical
p.000033: trial reports are prepared and provided to the regulatory agency(ies) as r equired by the applicable
p.000033: regulatory requirement(s). The sponsor should also ensure that the cli n ic a l trial reports in
p.000033: marketing applications meet the standards of the note for guidance o n Structure and Content of
p.000033: Clinical S tudy Reports . (NOTE: The note for guidance on S tructure and Content of Clinical S
p.000033: tudy Reports specifies that abbreviated study reports may be acceptable in certain cases.)
p.000033:
p.000033: 5.23 Multicentre Trials
p.000033: For multicentre trials, the sponsor should ensure that:
p.000033: 5.23.1 All investigators conduct the trial in strict compliance with the protocol agreed to by the
p.000033: sponsor and, if required, by the regulatory authority(ies), and gi ven approval/favourable opinion by the
p.000033: IRB/IEC.
p.000033: 5.23.2 The CRFs are designed to capture the required data at all multicentre trial sites. For
p.000033: those investigators who are collecting additional data, supplemental CRFs should also be provided
p.000033: that are designed to capture the additional data.
p.000033: 5.23.3 The responsibilities of co-ordinating investigator(s) and the other partici pating
p.000033: investigators are documented prior to the start of the trial.
p.000033: 5.23.4 All investigators are given instructions on following the protocol, on complying with a
p.000033: uniform set of standards for the assessment of clinical and laboratory findings, and o n
p.000033: completing the CRFs.
p.000033: 5.23.5 Communication between investigators is facilitated.
p.000033:
p.000033:
p.000033:
p.000033:
p.000034: 34
p.000034:
p.000034: _____________________________________________________________ 3CC1a ■
p.000034:
p.000034:
p.000034:
p.000034: 6. CLINICAL TRIAL P ROTOCOL AND P ROTOCOL AMENDMENT( S)
p.000034: The contents of a trial protocol should generally include the following topics. However, site
p.000034: specific information may be provided on separate protocol page(s), or addressed in a separate
p.000034: agreement, and some of the information listed below may be contained in other protocol
p.000034: referenced documents, such as an Investigator’s Brochure.
p.000034:
p.000034: 6.1 General Informa tio n
p.000034: 6.1.1 Protocol title, protocol identifying number, and date. Any amendment(s) should a l so bear the
p.000034: amendment number(s) and date(s).
p.000034: 6.1.2 Name and address of the sponsor and monitor (if other than the sponsor).
...
p.000046: protocol/amendment(s) and CRF
p.000046:
p.000046:
p.000046:
p.000046: To document the informed X X consent
p.000046:
p.000046:
p.000046: To document that subjects will be X X given appropriate
p.000046: written
p.000046: information (content and
p.000046: wording) to support their ability to give fully informed consent
p.000046: To document that recruitment X measures are appropriate and not
p.000046: coe rcive
p.000046: To document the financial X X agreement between the
p.000046: investigator/institution and the sponsor for the trial
p.000046: To document that compensation to X X subject(s) for trial-related
p.000046: injury
p.000046: will be available
p.000046: To document agreements
p.000046:
p.000046: X X
p.000046: X
p.000046: X (where
p.000046: required) X
p.000046: X X
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000047: 47
p.000047:
p.000047: ■ 3CC1a _____________________________________________________________
p.000047:
p.000047:
p.000047:
p.000047:
p.000047: Titl e of Document Pu rpose
p.000047: Located i n Files of
p.000047:
p.000047: Investigator/ I ns tit u tio n
p.000047: Sponso r
p.000047:
p.000047: 8.2.7 DATED, DOCUMENTED
p.000047: A PP ROVAL/ FAVOURAB LE
p.000047: OPINION OF INSTITUTIONAL REVIEW BOARD (IRB)/
p.000047: INDE P ENDENT ETHICS
p.000047: COMMITTEE (IEC) OF THE FOLLOWING:
p.000047: – protocol and any amendments
p.000047: – CRF (if applicable)
p.000047: – informed consent form(s)
p.000047: – any other written information to be provided to the subject(s)
p.000047: – advertisement for subject recruitment (if used)
p.000047: – subject compensation (if any)
p.000047: – any other documents given
p.000047: approval/ favourable opinion
p.000047: 8.2.8 INSTITUTIONAL REVIEW
p.000047: BOARD/INDE P ENDENT ETHICS COMMITTEE COMPOSITION
p.000047: To document that the trial has been subject to IRB/IEC review and given approval/favourable
p.000047: opinion. To identify the version number and date of the
p.000047: document(s)
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047: To document that the IRB/IEC is constituted in agreement with GCP
p.000047: X X
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047: X X
p.000047: (where required)
p.000047:
p.000047: 8.2.9 REGULATORY
p.000047: AU THORITY(IES)
p.000047: AUTHORISATION/ A PP ROVAL/ NOTIFICATION OF P ROTOCOL
p.000047: (where required)
p.000047: To document appropriate authorisation/approval/
p.000047: notification by the regulatory
p.000047: authority(ies) has been obtained prior to initiation of the trial in compliance with the applicable
p.000047: regulatory requirement(s)
p.000047: X
p.000047: (where required)
p.000047: X
p.000047: (where required)
p.000047:
p.000047: 8.2.10 CURRICULUM VITAE AND/OR OTHER RELEVANT
p.000047: DOCUMENTS EVIDENCING QUALIFICATIONS OF
p.000047: INVESTIGATOR( S) AND SUB- INVESTIGATOR( S)
p.000047: 8.2.11 NORMAL VALUE( S)/ RANGE( S) FOR MEDICAL/
p.000047: LA B ORATORY/TECHNICAL P ROCEDURE( S) AND/OR
p.000047: TEST( S) INCLUDED IN THE PROTOCOL
p.000047: To document qualifications and X X eligibility to conduct
p.000047: trial and/or
p.000047: provide medical supervision of subjects
p.000047:
p.000047:
...
p.000048:
p.000048:
p.000048: 8.2.19 P r e-Trial Monitori ng R epo rt To document that the site is
p.000048: X
p.000048: suitable for the trial (may be combined with 8.2.20)
p.000048:
p.000048: 8.2.20 Trial In itiatio n Monitori ng R epo rt
p.000048: To document that trial procedures X X were reviewed with the
p.000048: investigator and the
p.000048: investigator’s trial staff ( may be combined with 8.2.19)
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000049: 49
p.000049:
p.000049: ■ 3CC1a _____________________________________________________________
p.000049:
p.000049:
p.000049:
p.000049: 8.3 During the Clinical Conduct of the Trial
p.000049: In addition to having on file the above documents, the following should be added to the file s during
p.000049: the trial as evidence that all new relevant information is documented as it becomes availa ble
p.000049:
p.000049:
p.000049: Titl e of Document Pu rpose
p.000049: Located i n Files of
p.000049:
p.000049: Investigator/ I ns tit u tio n
p.000049: Sponso r
p.000049:
p.000049: 8.3.1 INVESTIGATOR’S BROCHURE U P DATES
p.000049:
p.000049:
p.000049: 8.3.2 ANY REVISION TO:
p.000049: – protocol/amendment(s) and CRF
p.000049: – informed consent form
p.000049: – any other written information provided to subjects
p.000049: – advertisement for subject recruitment (if used)
p.000049: 8.3.3 DATED, DOCUMENTED
p.000049: A PP ROVAL/ FAVOURAB LE
p.000049: OPINION OF INSTITUTIONAL REVIEW BOARD (IRB)
p.000049: /INDE P ENDENT ETHICS
p.000049: COMMITTEE (IEC) OF THE FOLLOWING:
p.000049: – protocol amendment(s)
p.000049: – revision(s) of:
p.000049: – informed consent form
p.000049: – any other written
p.000049: information to be provided to the subject
p.000049: – advertisement for subject recruitment (if used)
p.000049: – any other documents given
p.000049: approval/favourable opinion
p.000049: – continuing review of trial (where required)
p.000049: To document that investigator is X X informed in a t imely
p.000049: manner of
p.000049: relevant information as i t becomes available
p.000049: To document revisions of these X X trial related documents
p.000049: that take
p.000049: effect during trial
p.000049:
p.000049:
p.000049:
p.000049:
p.000049:
p.000049:
p.000049:
p.000049:
p.000049: To document that the X X amendment(s)
p.000049: and/or revision(s)
p.000049: have been subject to IRB/IEC review and were given
p.000049: approval/favourable opinion. To identify the version number and date of the document(s).
p.000049:
p.000049: 8.3.4 REGULATORY
p.000049: AU THORITY(IES)
p.000049: AU THORI SATIONS/A PP ROVAL S
p.000049: / NOTIFICATIONS WHERE REQUIRED FOR:
p.000049: – protocol amendment(s) and other documents
p.000049: To document compliance with applicable regulatory
p.000049: requirements
p.000049: X X
p.000049: (where required)
p.000049:
p.000049: 8.3.5 CURRICULUM VITAE FOR NEW INVESTIGATOR( S) AND/OR
p.000049: SUB-INVESTIGATOR( S)
p.000049: (see 8.2.10) X X
p.000049:
p.000049:
p.000049:
p.000049:
p.000049:
p.000050: 50
p.000050:
p.000050: _____________________________________________________________ 3CC1a ■
p.000050:
p.000050:
p.000050:
p.000050:
p.000050: Titl e of Document Pu rpose
p.000050: Located i n Files of
p.000050:
p.000050:
p.000050:
p.000050:
p.000050: 8.3.6 U P DATES TO NORMAL
p.000050: VALUE( S)/RANGE( S) FOR MEDICAL/ LABORATORY/ TECHNICAL
p.000050: P ROCEDURE( S)/TEST( S)
p.000050: INCLUDED IN THE P ROTOCOL
p.000050:
p.000050:
p.000050:
p.000050: To document normal values and ranges that are revised during the trial (see 8.2.11)
p.000050: Investigator/ I ns tit u tio n
p.000050: X X
p.000050: Sponso r
p.000050:
p.000050: 8.3.7 U P DATES OF MEDICAL/
p.000050: LA B ORATORY/TECHNICAL P ROCEDURES/TESTS
p.000050: – certification or
p.000050: – accreditation or
p.000050: – established quality control and/or external quality
p.000050: assessment or
p.000050: – other validation (where required)
p.000050: To document that tests remain adequate throughout the trial
...
General/Other / Incapacitated
Searching for indicator incapacity:
(return to top)
p.000010: All those planned and systematic actions that are established to ensure that the trial i s
p.000010: performed and the data are generated, documented (recorded), and reported in com pli ance with Good
p.000010: Clinical Practice (GCP) and the applicable regulatory requirement(s).
p.000010:
p.000010: 1.47 Quality Control (QC)
p.000010: The operational techniques and activities undertaken within the quality assurance system to verify that
p.000010: the requirements for quality of the trial-related activities have been fulfilled.
p.000010:
p.000010: 1.48 Ra ndom isatio n
p.000010: The process of a ssigning trial subjects to treatment or control groups using an element of chance
p.000010: to determine the assignments in order to reduce bias.
p.000010:
p.000010: 1.49 R egulatory Au t horities
p.000010: Bodies having the power to regulate. In this GCP guideline the expression Regulatory
p.000010: Authorities includes the authorities that review submitted clinical data and those that
p.000010: conduct inspections (see 1.29). These bodies are sometimes referred to as competent
p.000010: authorities.
p.000010:
p.000010: 1.50 Serious Adverse Event ( SAE) or Serious Adverse Drug Reaction ( Serious ADR)
p.000010: Any untoward medical occurrence that at any dose:
p.000010: • results in death,
p.000010: • is life-threatening,
p.000010: • requires inpatient hospitalisation or prolongation of existing hospitalisation,
p.000010: • results in persistent or significant disability/incapacity, or
p.000010: • is a congenital anomaly/birth defect
p.000010: (see the note for guidance on Clinical Safety Data Management: Definitions and Standards fo r Expedited
p.000010: Reporting ).
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: ■ 3CC1a _____________________________________________________________
p.000011:
p.000011:
p.000011:
p.000011: 1.51 Source Data
p.000011: All information in original records and certified copies of original records of cli n ic a l
p.000011: findings, observations, or other activities in a clinical trial necessary for the reconstruction and
p.000011: evaluation of the trial. Source data are contained in source documents (original recor ds or certified
p.000011: copies).
p.000011:
p.000011: 1.52 Source Documents
p.000011: Original documents, data, and records (e.g., hospital records, clinical and office charts,
p.000011: laboratory notes, memoranda, subjects' diaries or evaluation checklists, p harmacy
p.000011: dispensing records, recorded data from automated instruments, copies or transcriptions certified
p.000011: after verification as being accurate copies, microfiches, photographic negatives, microfilm or
p.000011: magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at
p.000011: medico-technical departments involved in the clinical trial).
p.000011:
p.000011: 1.53 Sponsor
p.000011: An individual, company, institution, or organisation which takes responsibility for the
p.000011: initiation, management, and/or financing of a clinical trial.
p.000011:
p.000011: 1.54 Sponsor-Inves tigator
...
General/Other / Natural Hazards
Searching for indicator hazard:
(return to top)
p.000017: other written information to be provided to subjects.
p.000017: 4.4.2 As part of the investigator’s/institution’s written application to the IRB/IEC, the
p.000017: investigator/institution should provide the IRB/IEC with a current copy of the I nves tigator' s Brochure.
p.000017: If the Investigator's Brochure is updated during the trial, the
p.000017: investigator/institution should supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
p.000017: 4.4.3 During the trial the investigator/institution should provide to the IRB/IEC a l l
p.000017: documents subject to review.
p.000017:
p.000017: 4.5 Compliance w it h P rotocol
p.000017: 4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed
p.000017: to by the sponsor and, if required, by the regul atory authority(ies) and which was given
p.000017: approval/favourable opinion by the IRB/IEC. The investigator/institution and the sponsor should
p.000017: sign the protocol, or an alternative contract, to confirm agreement.
p.000017: 4.5.2 The investigator should not implement any deviation from, or changes of the protocol without
p.000017: agreement by the sponsor and prior review and documented approval/favourable opinion from the
p.000017: IRB/IEC of an amendment, except where necessary to eliminate a n immediate hazard(s) to
p.000017: trial su bjects, or when the change(s) involves only logistical or administrative aspects of
p.000017: the trial (e.g., change in monitor(s), change of telephone num be r(s)).
p.000017: 4.5.3 The investigator, or person designated by the investigator, should document a nd
p.000017: explain any deviation from the approved protocol.
p.000017: 4.5.4 The investigator may implement a deviation from, or a change of, the protocol to
p.000017: eliminate an immediate hazard(s) to trial subjects without prior
p.000017: IRB/IEC
p.000017:
p.000018: 18
p.000018:
p.000018: _____________________________________________________________ 3CC1a ■
p.000018:
p.000018:
p.000018:
p.000018: approval/favourable opinion. As soon as possible, the i mplemented deviation or change, the reasons
p.000018: for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:
p.000018: a) to the IRB/IEC for review and approval/favourable opinion,
p.000018: b) to the sponsor for agreement and, if required, c ) to the regulatory authority(ies).
p.000018:
p.000018: 4.6 Inves tigatio nal P roduct( s)
p.000018: 4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests
p.000018: with the investigator/institution.
p.000018: 4.6.2 Where allowed/required, the investigator/institution may/should assign some or a l l of the
p.000018: investigator’s/institution’s duties for investigational product(s) accountability at the trial site(s)
p.000018: to an appropriate pharmacist or another appropriate individual who is under the supervision of the
p.000018: investigator/institution.
p.000018: 4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who
p.000018: is designated by the investigator/institution, should maintain records of the product's
p.000018: delivery to the trial site, the inventory at the site, the use by each subject, and the return to
p.000018: the
...
General/Other / Public Emergency
Searching for indicator emergency:
(return to top)
p.000012:
p.000012:
p.000012: 1.60 Unexpected Adverse Drug Reaction
p.000012: An adverse reaction, the nature or severity of which is not consistent with the applicable
p.000012: product information (e.g., Investigator's Brochure for an unapproved investigational product or package
p.000012: insert/summary of product characteristics for an a pproved product) (see note for guidance on Clinical
p.000012: Safety Data Management: Definitions and Standards for Expedited Reporting ).
p.000012:
p.000012: 1.61 Vulnerable Subjec ts
p.000012: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
p.000012: expectation, whether justified or not, of benefits associated with participation, or of a
p.000012: retaliatory response from senior members of a hierarchy in case of refusal to participate.
p.000012: Examples are members of a group with a hierarchical structure, such as medical, p harmacy, dental, and
p.000012: nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
p.000012: industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
p.000012: include patients with in curable diseases, persons in nur s i n g homes, unemployed or
p.000012: impoverished persons, patients in emergency situations, ethnic minority groups, homeless
p.000012: persons, nomads, refugees, minors, and those incapable of giving consent.
p.000012:
p.000012: 1.62 Well-being ( of the trial subjects)
p.000012: The physical and mental integrity of the subjects participating in a clinical trial.
p.000012:
p.000012:
p.000012:
p.000012: 2. THE PRINCIPLES OF ICH GCP
p.000012: 2.1 Clinical trials should be conducted in accordance with the ethical principles that
p.000012: have their origin in the Declaration of Helsinki, and that are consistent with GCP and the
p.000012: applicable regulatory requirement(s).
p.000012: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
p.000012: against the anticipated benefit for the individual trial subject and society. A trial should be
p.000012: initiated and continued only if the anticipated benefits justify the risks.
p.000012: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000012: considerations and should prevail over interests of science and society.
p.000012: 2.4 The available nonclinical and clinical information on an investigational product
p.000012: should be adequate to support the proposed clinical trial.
p.000012:
p.000012:
p.000013: 13
p.000013:
...
p.000021: anticipated direct clinical benefit to the subject), should be conducted in subjects who
p.000021: personally give consent and who sign and date the written informed consent form.
p.000021: 4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a leg a lly
p.000021: acceptable representative provided the following conditions are fulfilled:
p.000021: a) The objectives of the trial can not be met by means of a trial in subjects who can give
p.000021: informed consent personally.
p.000021: b) The foreseeable risks to the subjects are low.
p.000021: c ) The negative impact on the subject’s well-being is minimised and low. d) The trial is not
p.000021: prohibited by law.
p.000021: e) The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such
p.000021: subjects, and the written approval/ favourable opinion covers this aspect.
p.000021: Such trials, unless an exception is justified, should be conducted in patients having a
p.000021: disease or condition for which the investigational product is intended. Subjects in these
p.000021: trials should be particularly closely monitored and should be withdrawn if they appear to be unduly
p.000021: distressed.
p.000021: 4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the
p.000021: subject's legally acceptable representative, if present, should be requested. When prior consent of
p.000021: the subject is not possible, and the subject’s legally acceptable representative is not
p.000021: available, enrolment of the subject should require measures described in the protocol and/or elsewhere,
p.000021: with documented approval/favourable opinion by the IRB/IEC, to protect the rights, safety and
p.000021: well-being of the subject and to ensure compliance with applicable regulatory requirements. The
p.000021: subject or the subject's legally acceptable representative should be informed about the trial
p.000021: as soon as possible and consent to continue and other consent as appropriate (see 4.8.10) should be
p.000021: requested.
p.000021:
p.000021: 4.9 Records and Reports
p.000021: 4.9.1 The investigator should ensure the accuracy, completeness, legibility, and t imeliness of the
p.000021: data reported to the sponsor in the CRFs and in all required reports.
p.000021: 4.9.2 Data reported on the CRF, that are derived from source documents, should be
p.000021: consistent with the source documents or the discrepancies should be explained.
...
p.000027: 5.13 Manufacturing, P ackaging, Labelling, and Coding Inves tigatio nal P roduct( s)
p.000027: 5.13.1 The sponsor should ensure that the investigational product(s) (inclu ding active
p.000027: comparator(s) and placebo, if applicable) is characterised as appropriate to the stage of
p.000027: development of the product(s), is manufactured in accordance with any applicable GMP, a nd
p.000027: is coded and labelled in a manner that protects the blinding, if applicable. In addition, the
p.000027: labelling should comply with applicable regulatory requirement(s).
p.000027: 5.13.2 The sponsor should determine, for the investigational product(s), acceptable s torage
p.000027: temperatures, storage conditions (e.g. protection from light), s torage times, reconstitution fluids
p.000027: and procedures, and devices for product infusion, if any. The sponsor should i n fo rm all involved
p.000027: parties (e.g. monitors, investigators, pharmacists, s torage managers) of these de t ermination s.
p.000027: 5.13.3 The investigational product(s) should be packaged to prevent contamination a nd
p.000027: unacceptable deterioration during transport and s torage.
p.000027:
p.000028: 28
p.000028:
p.000028: _____________________________________________________________ 3CC1a ■
p.000028:
p.000028:
p.000028:
p.000028: 5.13.4 In blinded trials, the coding system for the investigational product(s) should i ncl u de a
p.000028: mechanism that permits rapid identification of the product(s) in case of a m edica l
p.000028: emergency, but does not permit undetectable breaks of the blinding.
p.000028: 5.13.5 If significant formulation changes are made in the investigational or comparator
p.000028: product(s) during the course of clinical development, the results of any additional studies of the
p.000028: formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether
p.000028: these changes would significantly alter the pharmacokinetic profile of the product should be
p.000028: available prior to the use of the new formulation in clinical trials.
p.000028:
p.000028: 5.14 Supplying and Ha ndling Inves tigatio nal P roduct( s)
p.000028: 5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the
p.000028: investigational product(s).
p.000028: 5.14.2 The sponsor should not supply an investigator/institution with the inves tigational
p.000028: product(s) until the sponsor obtains all required documentation (e.g. approval/favourable opinion
p.000028: from IRB/IEC and regulatory authority(ies)).
p.000028: 5.14.3 The sponsor should ensure that written procedures include instructions that the
p.000028: investigator/institution should follow for the handling and storage of inves tigational
p.000028: product(s) for the trial and documentation thereof. The procedures should address adequate and safe
p.000028: receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of
p.000028: unused investigational product(s) to the sponsor (or alternative disposition i f authorised by the
...
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: Titl e of Document Pu rpose
p.000048:
p.000048: Located i n Files of
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: 8.2.13 SAMPLE OF LABEL( S) ATTACHED TO
p.000048: INVESTIGATIONAL P RODUCT CONTAINER( S)
p.000048:
p.000048:
p.000048:
p.000048: To document compliance with
p.000048: applicable labelling regulations and appropriateness of
p.000048: instructions provided to the subjects
p.000048: Investigator/ I ns tit u tio n
p.000048: Sponso r
p.000048:
p.000048:
p.000048: X
p.000048:
p.000048: 8.2.14 INSTRUCTIONS FOR HANDLING OF
p.000048: INVESTIGATIONAL
p.000048: P RODUCT( S) AND TRIAL- RELATED MATERIALS
p.000048: (if not included in protocol or Investigator’s Brochure)
p.000048: 8.2.15 SHIPPING RECORDS FOR INVESTIGATIONAL
p.000048: P RODUCT( S) AND TRIAL- RELATED MATERIALS
p.000048:
p.000048:
p.000048:
p.000048: 8.2.16 CERTIFICATE( S) OF ANALYSIS OF INVESTIGATIONAL
p.000048: P RODUCT( S) SHI PP ED
p.000048: 8.2.17 DECODING P ROCEDURES FOR BLINDED TRIALS
p.000048: To document instructions needed to ensure proper storage,
p.000048: packaging, dispensing and
p.000048: disposition of investigational products and trial-related
p.000048: mat e r i a ls
p.000048:
p.000048:
p.000048: To document shipment dates, batch numbers and method of shipment of investigational product(s) and
p.000048: trial-related
p.000048: materials. Allows tracking of
p.000048: product batch, review of shipping conditions, and accountability
p.000048: To document identity, purity, and strength of investigational
p.000048: product(s) to be used in the trial
p.000048: To document how, in case of an emergency, identity of blinded investigational product can be
p.000048: revealed without breaking the
p.000048: blind for the remaining subjects' treatment
p.000048: X X
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: X X
p.000048: (third party if applicable)
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: X
p.000048:
p.000048: 8.2.18 Master Ra ndom isatio n List To document method for
p.000048: randomisation of trial population
p.000048: X
p.000048: (third party if applicable)
p.000048:
p.000048:
p.000048: 8.2.19 P r e-Trial Monitori ng R epo rt To document that the site is
p.000048: X
p.000048: suitable for the trial (may be combined with 8.2.20)
p.000048:
p.000048: 8.2.20 Trial In itiatio n Monitori ng R epo rt
p.000048: To document that trial procedures X X were reviewed with the
p.000048: investigator and the
p.000048: investigator’s trial staff ( may be combined with 8.2.19)
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000049: 49
p.000049:
p.000049: ■ 3CC1a _____________________________________________________________
p.000049:
p.000049:
p.000049:
p.000049: 8.3 During the Clinical Conduct of the Trial
p.000049: In addition to having on file the above documents, the following should be added to the file s during
...
General/Other / Relationship to Authority
Searching for indicator authority:
(return to top)
p.000007: other things, reviewing and approving / providing favourable opinion on, the trial protocol,
p.000007:
p.000008: 8
p.000008:
p.000008: _____________________________________________________________ 3CC1a ■
p.000008:
p.000008:
p.000008:
p.000008: the suitabi lity of the investigator(s), facilities, and the methods and material to be used i n
p.000008: obtaining and documenting informed consent of the trial subjects.
p.000008: The legal status, composition, function, operations and regulatory requirements pe rtaining to
p.000008: Independent Ethics Committees may differ among countries, but should allow the
p.000008: Independent Ethics Committee to act in agreement with GCP as described in this guideline.
p.000008:
p.000008: 1.28 Informed Consent
p.000008: A process by which a subject voluntarily confirms his or her willingness to participate in a
p.000008: particular trial, after having been informed of all aspects of the trial that are relevant to the
p.000008: subject's decision to participate. Informed consent is documented by means of a written, signed
p.000008: and dated informed consent form.
p.000008:
p.000008: 1.29 Inspec tio n
p.000008: The act by a regul atory authority(ies) of conducting an official review of documents,
p.000008: facilities, records, and any other resources that are deemed by the authority(ies) to be related to
p.000008: the clinical trial and that may be l ocated at the site of the trial, at the sponsor’s and/or
p.000008: contract research org anisation’s (CRO’s) facilities, or at other establishments dee med
p.000008: appropriate by the regulatory authority(ies).
p.000008:
p.000008: 1.30 Ins tit u tio n ( med ical)
p.000008: Any public or private entity or agency or medical or dental facility where clinical trials are
p.000008: conducted.
p.000008:
p.000008: 1.31 Institutional Revie w Board (IRB)
p.000008: An independent body constituted of medical, scientific, and non-scientific members, whose
p.000008: responsibility is to ensure the protection of the rights, safety and well-being of human
p.000008: subjects involved in a trial by, among other things, reviewing, approving, and p roviding
p.000008: continuing review of trial protocol and amendments and of the methods and material to be used in
p.000008: obtaining and documenting informed consent of the trial subjects.
p.000008:
p.000008: 1.32 Int erim Clinical Trial/Study Report
p.000008: A report of intermediate results and their evaluation based on analyses performed d ur i n g the
p.000008: course of a trial.
p.000008:
p.000008: 1.33 Inves tigatio nal P roduct
p.000008: A pharmaceutical form of an active ingredient or placebo being tested or used as a r efe r e nce in
p.000008: a clinical trial, including a product with a marketing a uthorisation when used or
p.000008: assembled (formulated or packaged) in a way different from the a pproved form, or when used for
p.000008: an unapproved indic ation, or when used to gain further information about a n approved use.
p.000008:
p.000008:
p.000008:
p.000008:
p.000008:
p.000009: 9
p.000009:
...
p.000014: should vote/provide opinion on a trial-related matter.
p.000014: A lis t of IRB/IEC members and their qualifications should be maintained.
p.000014: 3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should
p.000014: maintain written records of its activities and minutes of its meetings, and should comply with
p.000014: GCP and with the applicable regulatory requirement(s).
p.000014:
p.000014:
p.000014:
p.000015: 15
p.000015:
p.000015: ■ 3CC1a _____________________________________________________________
p.000015:
p.000015:
p.000015:
p.000015: 3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum,
p.000015: as stipulated in its written operating procedures, is present.
p.000015: 3.2.4 Only members who participate in the IRB/IEC review and discussion should
p.000015: vote/provide their opinion and/or advise.
p.000015: 3.2.5 The investigator may provide information on any aspect of the trial, but should not
p.000015: participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
p.000015: 3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
p.000015:
p.000015:
p.000015: 3.3 P rocedur es
p.000015: The IRB/IEC should establish, document in writing, and follow its procedures, which should i nclu de:
p.000015: 3.3.1 Determining its composition (names and qualifications of the members) and the authority
p.000015: under which it is established.
p.000015: 3.3.2 Scheduling, notifying i t s members of, and conducting i t s meetings.
p.000015: 3.3.3 Conducting initial and continuing review of trials.
p.000015: 3.3.4 De termining the frequency of continuing review, as appropriate.
p.000015: 3.3.5 Providing, according to the applicable regulatory requirements, expedited review and
p.000015: approval/favourable opinion of minor change(s) in ongoing trials that have the
p.000015: approval/favourable opinion of the IRB/IEC.
p.000015: 3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its
p.000015: written approval/favourable opinion of the trial.
p.000015: 3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated
p.000015: without prior written IRB/IEC approval/favourable opinion of an appropriate am e n d m e nt, except
p.000015: when necessary to eliminate immediate hazards to the subjects or when the chan ge( s) involves only
p.000015: logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s))
p.000015: (see 4.5.2).
p.000015: 3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
p.000015: a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial
p.000015: subjects (see 3.3.7, 4.5.2, 4.5.4).
p.000015: b) Changes increasing the r isk to subjects and/or affecting significantly the conduct
p.000015: of the trial (see 4.10.2).
p.000015: c ) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000015: d) New information that may affect adversely the safety of the subjects or the
p.000015: conduct of the trial.
p.000015: 3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution conce rn
p.000015: i n g:
p.000015: a) I t s trial-related decisions/opinions.
p.000015: b) The reasons for i t s decisions/opinions.
p.000015: c ) Procedures for appeal of i t s decisions/opinions.
p.000015:
p.000015:
p.000015:
p.000016: 16
p.000016:
p.000016: _____________________________________________________________ 3CC1a ■
p.000016:
p.000016:
p.000016:
p.000016: 3.4 R eco rds
p.000016: The IRB/IEC should retain all relevant records (e.g., written procedures, membership li s t s, lis t s
p.000016: of occupations/affiliations of members, submitted documents, minutes of meetings, a nd correspondence) for
p.000016: a period of at least 3 years after completion of the trial and make them available upon request
p.000016: from the regulatory authority(ies).
p.000016: The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written
p.000016: procedures and membership lis t s.
p.000016:
p.000016:
p.000016: 4. INVESTIGATOR
p.000016: 4.1 Inves tigator’s Qualifications and Agreemen ts
p.000016: 4.1.1 The investigator(s) should be qualified by education, training, and experience to
p.000016: assume responsibility for the proper conduct of the trial, should meet all the q ualification s
p.000016: specified by the applicable regulatory requirement(s), and should provide evidence of such
p.000016: qualifications through up-to-date curriculum vitae and/or other relevant documentation requested
p.000016: by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).
p.000016: 4.1.2 The investigator should be thoroughly familiar with the appropriate use of the
p.000016: investigational product(s), as described in the protocol, in the current I nves tigator' s
p.000016: Brochure, in the product information and in other information sources provided by the
p.000016: sponsor.
p.000016: 4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable regulatory
p.000016: requirements.
p.000016: 4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and
p.000016: inspection by the appropriate regulatory authority(ies).
p.000016: 4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the
p.000016: investigator has delegated significant trial-related duties.
p.000016:
p.000016: 4.2 Adequate R esources
p.000016: 4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective data) a
p.000016: potential for recruiting the required number of suitable subjects within the agreed
p.000016: recruitment period.
p.000016: 4.2.2 The investigator should have sufficient time to properly conduct and complete the trial
p.000016: within the agreed trial period.
p.000016: 4.2.3 The investigator should have available an adequate number of qualified staff a nd
p.000016: adequate facilities for the foreseen duration of the trial to conduct the trial properly a nd
p.000016: s afely.
p.000016: 4.2.4 The investigator should ensure that all persons assisting with the trial
p.000016: are adequately informed about the protocol, the investigational product(s), and their trial-related duties
p.000016: and functions.
p.000016:
p.000016:
p.000016:
p.000016:
p.000016:
p.000016:
p.000017: 17
p.000017:
p.000017: ■ 3CC1a _____________________________________________________________
p.000017:
p.000017:
p.000017:
p.000017: 4.3 Medical Care of Trial Subjects
p.000017: 4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub-
p.000017: investigator for the trial, should be responsible for all trial-related medical (or de ntal)
p.000017: decision s .
p.000017: 4.3.2 During and following a subject’s participation in a trial, the investigator/institution should
...
p.000017: rawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the
p.000017: reason(s), while fully respecting the subject’s rights.
p.000017:
p.000017: 4.4 Communication w it h IRB/IEC
p.000017: 4.4.1 Before initiating a trial, the investigator/institution should have written and dated
p.000017: approval/favourable opinion from the IRB/IEC for the trial protocol, written i nform ed
p.000017: consent form, consent form updates, subject recruitment procedures (e.g., advertisements), and any
p.000017: other written information to be provided to subjects.
p.000017: 4.4.2 As part of the investigator’s/institution’s written application to the IRB/IEC, the
p.000017: investigator/institution should provide the IRB/IEC with a current copy of the I nves tigator' s Brochure.
p.000017: If the Investigator's Brochure is updated during the trial, the
p.000017: investigator/institution should supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
p.000017: 4.4.3 During the trial the investigator/institution should provide to the IRB/IEC a l l
p.000017: documents subject to review.
p.000017:
p.000017: 4.5 Compliance w it h P rotocol
p.000017: 4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed
p.000017: to by the sponsor and, if required, by the regul atory authority(ies) and which was given
p.000017: approval/favourable opinion by the IRB/IEC. The investigator/institution and the sponsor should
p.000017: sign the protocol, or an alternative contract, to confirm agreement.
p.000017: 4.5.2 The investigator should not implement any deviation from, or changes of the protocol without
p.000017: agreement by the sponsor and prior review and documented approval/favourable opinion from the
p.000017: IRB/IEC of an amendment, except where necessary to eliminate a n immediate hazard(s) to
p.000017: trial su bjects, or when the change(s) involves only logistical or administrative aspects of
p.000017: the trial (e.g., change in monitor(s), change of telephone num be r(s)).
p.000017: 4.5.3 The investigator, or person designated by the investigator, should document a nd
p.000017: explain any deviation from the approved protocol.
p.000017: 4.5.4 The investigator may implement a deviation from, or a change of, the protocol to
p.000017: eliminate an immediate hazard(s) to trial subjects without prior
p.000017: IRB/IEC
p.000017:
p.000018: 18
p.000018:
p.000018: _____________________________________________________________ 3CC1a ■
p.000018:
p.000018:
p.000018:
p.000018: approval/favourable opinion. As soon as possible, the i mplemented deviation or change, the reasons
p.000018: for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:
p.000018: a) to the IRB/IEC for review and approval/favourable opinion,
p.000018: b) to the sponsor for agreement and, if required, c ) to the regulatory authority(ies).
p.000018:
p.000018: 4.6 Inves tigatio nal P roduct( s)
p.000018: 4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests
p.000018: with the investigator/institution.
p.000018: 4.6.2 Where allowed/required, the investigator/institution may/should assign some or a l l of the
p.000018: investigator’s/institution’s duties for investigational product(s) accountability at the trial site(s)
p.000018: to an appropriate pharmacist or another appropriate individual who is under the supervision of the
p.000018: investigator/institution.
p.000018: 4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who
p.000018: is designated by the investigator/institution, should maintain records of the product's
p.000018: delivery to the trial site, the inventory at the site, the use by each subject, and the return to
p.000018: the
p.000018: sponsor or alternative disposition of unused product(s). These records should include dates, quantities,
p.000018: batch/serial numbers, expiration dates (if applicable), and the unique code numbers
p.000018: assigned to the investigational product(s) and trial subjects. Investigators should maintain records
p.000018: that document adequately that the subjects were provided the doses specified by the
p.000018: protocol and reconcile all investigational product(s) received from the sponsor.
p.000018: 4.6.4 The investigational product(s) should be s tored as specified by the sponsor (see 5.13.2 and
p.000018: 5.14.3) and in accordance with applicable regulatory requirement(s).
...
p.000020: trial procedures to be followed, including all invasive procedures.
p.000020: e) The subject's responsibilities.
p.000020: f ) Those aspects of the trial that are experimental.
p.000020: g ) The reasonably foreseeable r isks or inconveniences to the subject and, when
p.000020: applicable, to an embryo, foetus, or nursing infant.
p.000020: h) The reasonably expected benefits. When there is no intended clinical benefit to the
p.000020: subject, the subject should be made aware of this.
p.000020: i ) The alternative procedure(s) or course(s) of treatment that may be available to the
p.000020: subject, and their important potential benefits and risks.
p.000020: j ) The compensation and/or treatment available to the subject in the event of trial-related i n j
p.000020: ur y.
p.000020: k ) The anticipated prorated payment, if any, to the subject for participating in the trial. l )
p.000020: The anticipated expenses, if any, to the subject for participating in the trial.
p.000020: m ) That the subject's participation in the trial is voluntary and that the subject may refuse
p.000020: to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which
p.000020: the subject is otherwise entitled.
p.000020: n ) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be
p.000020: granted direct access to the subject's original medical records for verification of clinical
p.000020: trial procedures and /or data, without violating the confidentiality of the subject, to the
p.000020: extent permitted by the applicable laws and regulations and that, by signing a written informed
p.000020: consent form, the subject or the subject's legally acceptable representative is authorising such access.
p.000020: o) That records identifying the subject will be kept confident ial and, to the
p.000020: extent permitted by the applicable laws and/or regulations, will not be made p ublicly
p.000020: available. If the results of the trial are published, the subject’s identity will r e ma i n
p.000020: confide ntial.
p.000020: p) That the subject or the subject's legally acceptable representative will be informed in a t
p.000020: imely manner if information becomes available that may be relevant to the s ubject's willingness to
p.000020: continue participation in the trial.
p.000020: q) The person(s) to contact for further information regarding the trial and the rights of
p.000020: trial subjects, and whom to contact in the event of trial-related injury.
p.000020: r ) The foreseeable circumstances and/or reasons under which the subject's participation in the
p.000020: trial may be terminated.
p.000020: s) The expected duration of the subject's participation in the trial.
...
p.000022: are documented, are necessary, and are endorsed by the investigator. The investigator should
p.000022: retain records of the changes and corrections.
p.000022: 4.9.4 The investigator/institution should maintain the trial documents as specified i n
p.000022: Essential Documents for the Conduct of a Clinical Trial (see 8.) and as required by the
p.000022: applicable regulatory requirement(s). The investigator/institution should take measures to prevent
p.000022: accidental or premature destruction of these documents.
p.000022: 4.9.5 Essential documents should be retained until at least 2 years after the last approval of a
p.000022: marketing application in an ICH region and until there are no pending or contemplated marketing
p.000022: applications in an ICH region or at least 2 years have elapsed since the fo rma l discontinuation
p.000022: of clinical development of the investigational product. These documents should be retained for
p.000022: a longer period however if required by the applicable regulatory requirements or by an
p.000022: agreement with the sponsor. It is the responsibility of the sponsor to inform the
p.000022: investigator/institution as to when these documents no longer need to be retained (see 5.5.12).
p.000022: 4.9.6 The financial aspects of the trial should be documented in an agreement between the sponsor
p.000022: and the investigator/institution.
p.000022: 4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the
p.000022: investigator/institution should make available for direct access all requ ested trial-related recor
p.000022: ds.
p.000022:
p.000022: 4.10 Progress Reports
p.000022: 4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC
p.000022: annually, or more frequently, if requested by the IRB/IEC.
p.000022: 4.10.2 The investigator should promptly provide written rep orts to the sponsor, the IRB/IEC (see
p.000022: 3.3.8) and, where applicable, the institution on any changes significantly affecting the conduct of
p.000022: the trial, and/or increasing the risk to subjects.
p.000022:
p.000022: 4.11 Safety Reporting
p.000022: 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except
p.000022: for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies
p.000022: as not needing immediate reporting. The immediate reports should be followed promptly by
p.000022: detailed, written reports. The immediate and follow-up reports should ide ntify subjects by unique
p.000022: code numbers assigned to the trial subjects rather than by the subjects’ names, personal
p.000022: identification numbers, and/or addresses. The investigator should a l so comply with the applicable
p.000022: regulatory requirement(s) rel ated to the reporting of unexpected serious adverse drug reactions to
p.000022: the regulatory authority(ies) and the IRB/IEC.
p.000022: 4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as cr i t ica l to
p.000022: safety evaluations should be reported to the sponsor according to the reporting
p.000022: requirements and within the time periods specified by the sponsor in the protocol.
p.000022: 4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any
p.000022: additional requested information (e.g., autopsy reports and terminal medical reports).
p.000022:
p.000022:
p.000022:
p.000022:
p.000023: 23
p.000023:
p.000023: ■ 3CC1a _____________________________________________________________
p.000023:
p.000023:
p.000023:
p.000023: 4.12 Premature Termination or Suspension of a Trial
p.000023: If the trial is prematurely terminated or suspended for any reason,
p.000023: the
p.000023: investigator/institution should promptly inform the trial subjects, should assure appropr iate therapy
p.000023: and follow-up for the s ubjects, and, where required by the applicable regulatory requirement(s),
p.000023: should inform the regulatory authority(ies). In addition:
p.000023: 4.12.1 If the investigator terminates or suspends a trial without prior agreement of the
p.000023: sponsor, the investigator should inform the institution where applicable, and the
p.000023: investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the
p.000023: sponsor and the IRB/IEC a detailed written explanation of the termination or suspension.
p.000023: 4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should
p.000023: promptly inform the institution where applicable and the investigator/institution should promptly
p.000023: inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or
p.000023: suspension.
p.000023: 4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see
p.000023: 3.1.2 and 3.3.9), the investigator should inform the institution where applicable and the
p.000023: investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed
p.000023: written explanation of the termination or suspension.
p.000023:
p.000023: 4.13 Final Report( s) by Investigator
p.000023: Upon completion of the trial, the investigator, where applicable, should inform the
p.000023: institution; the investigator/institution should provide the IRB/IEC with a summ ary of the trial’s
p.000023: outcome, and the regulatory authority(ies) with any reports required.
p.000023:
p.000023:
p.000023: 5. S PONSOR
p.000023: 5.1 Quality Assurance and Quality Control
p.000023: 5.1.1 The sponsor is responsible for implementing and maintaining quality a ss urance and
p.000023: quality control systems with written SOPs to ensure that trials are conducted and data are generated,
p.000023: documented (recorded), and reported in compliance with the protocol, GCP, and the applicable
p.000023: regulatory requirement(s).
p.000023: 5.1.2 The sponsor is responsible for securing agreement from all involved parties to
p.000023: ensure direct access (see 1.21) to all trial related sites, source data/documents, and reports for
p.000023: the purpose of monitoring and auditing by the sponsor, and inspection by domestic a nd foreign
p.000023: regulatory authorities.
p.000023: 5.1.3 Quality control should be applied to each stage of data handling to ensure that a l l
p.000023: data are reliable and have been processed correctly.
p.000023: 5.1.4 Agreements, made by the sponsor with the investigator/institution and any other parties
p.000023: involved with the clinical trial, should be in writing, as part of the protocol or in a separate
p.000023: agreement.
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000024: 24
p.000024:
p.000024: _____________________________________________________________ 3CC1a ■
p.000024:
p.000024:
p.000024:
p.000024: 5.2 Contract Research Organisation (CRO)
p.000024: 5.2.1 A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a
...
p.000025: original data and observations with the processed data.
p.000025: 5.5.5 The sponsor should use an unambiguous subject identification c ode (see 1.58) that allows
p.000025: identification of all the data reported for each subject.
p.000025: 5.5.6 The sponsor, or other owners of the data, should retain all of the sponsor-specific
p.000025: essential documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical
p.000025: T r i a l).
p.000025: 5.5.7 The sponsor should retain all sponsor-specific essential documents in conformance with the
p.000025: applicable regulatory requirement(s) of the country(ies) where the product i s approved,
p.000025: and/or where the sponsor intends to apply for approval(s).
p.000025: 5.5.8 If the sponsor discontinues the clinical development of an investigational product (i.e.
p.000025: for any or all indications, routes of administration, or dosage forms), the sponsor should
p.000025: maintain all sponsor-specific essential documents for at least 2 years after fo rma l
p.000025: discontinuation or in conformance with the applicable regulatory requirement(s).
p.000025: 5.5.9 If the sponsor discontinues the clinical development of an investigational product, the sponsor
p.000025: should notify all the trial investigators/institutions and all the regulatory
p.000025: authorities.
p.000025: 5.5.10Any transfer of ownership of the data should be reported to the appropr
p.000025: iate authority(ies), as required by the applicable regulatory requirement(s).
p.000025: 5.5.11The sponsor specific essential documents should be retained until at least 2 years after the
p.000025: last approval of a marketing application in an ICH region and until there are no pending
p.000025: or contemplated marketing applications in an ICH region or at least 2 years have elapsed since
p.000025: the formal discontinuation of clinical development of the inves tigational product. These
p.000025: documents should be retained for a longer period however if required by the applicable regulatory
p.000025: requirement(s) or if needed by the sponsor.
p.000025: 5.5.12The sponsor should inform the investigator(s)/institution(s) in writing of the need for record
p.000025: retention and should notify the investigator(s)/institution(s) in writing when the tr i a l related
p.000025: records are no longer needed.
p.000025:
p.000025: 5.6 Investigator Selection
p.000025: 5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each
p.000025: investigator should be qualified by training and experience and should have adequate resources
p.000025: (see 4.1, 4.2) to properly conduct the trial for which the investigator is selected. If organisation
p.000025: of a co-ordinating committee and/or selection of co-ordinating inves tigator(s)
p.000025:
p.000026: 26
p.000026:
p.000026: _____________________________________________________________ 3CC1a ■
p.000026:
p.000026:
p.000026:
p.000026: are to be utilised in multicentre trials, their organisation and/or selection are the spon sor' s
p.000026: responsibility.
...
p.000026: document, to confirm this agreement.
p.000026:
p.000026: 5.7 Allocation of R espons ibiliti es
p.000026: Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related
p.000026: duties and functions.
p.000026:
p.000026: 5.8 Compensation to Subjects and Investigators
p.000026: 5.8.1 If required by the applicable regulatory requirement(s), the sponsor should provide
p.000026: insurance or should in de mnify (legal and financial coverage) the inves tigator/the
p.000026: institution against claims arising from the trial, except for claims that arise f r o
p.000026: m malpractice and/or negligence.
p.000026: 5.8.2 The sponsor's policies and procedures should address the costs of treatment of tr i a l
p.000026: subjects in the event of trial-related injuries in accordance with the applicable regulatory
p.000026: requirement(s).
p.000026: 5.8.3 When trial subjects receive compensation, the method and manner of compensation should comply
p.000026: with applicable regulatory requirement(s).
p.000026:
p.000026: 5.9 Financing
p.000026: The financial aspects of the trial should be documented in an agreement between the sponsor and the
p.000026: investigator/institution.
p.000026:
p.000026: 5.10 Notificatio n/Submission to R egulatory Au t hority( i es)
p.000026: Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, i f
p.000026: required by the applicable regulatory requirement(s)) should submit any required
p.000026: application(s) to the appropriate authority(ies) for review, acceptance, a nd/or permission ( as
p.000026: required by the applicable regulatory requirement(s)) to begin the trial(s). A n
p.000026: y
p.000026:
p.000026:
p.000027: 27
p.000027:
p.000027: ■ 3CC1a _____________________________________________________________
p.000027:
p.000027:
p.000027:
p.000027: notification/submission should be dated and contain sufficient information to identify the protocol.
p.000027:
p.000027: 5.11 Confirmation of Revie w by IRB/IEC
p.000027: 5.11.1 The sponsor should obtain from the investigator/institution:
p.000027: a) The name and address of the investigator's/institution’s IRB/IEC.
p.000027: b) A statement obtained from the IRB/IEC that it is organised and operates according to GCP
p.000027: and the applicable laws and regulations.
p.000027: c ) Documented IRB/IEC approval/favourable opinion and, if requested by the spons or, a current
p.000027: copy of protocol, written informed consent form(s) and any other written information to be
p.000027: provided to subjects, subject recruiting procedures, and documents related to payments and
p.000027: compensation available to the su bjects, and any other documents that the IRB/IEC may have
p.000027: requested.
p.000027: 5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s) in a ny aspect
p.000027: of the trial, such as modification(s) of the protocol, written informed consent form a nd any other
...
p.000027: unacceptable deterioration during transport and s torage.
p.000027:
p.000028: 28
p.000028:
p.000028: _____________________________________________________________ 3CC1a ■
p.000028:
p.000028:
p.000028:
p.000028: 5.13.4 In blinded trials, the coding system for the investigational product(s) should i ncl u de a
p.000028: mechanism that permits rapid identification of the product(s) in case of a m edica l
p.000028: emergency, but does not permit undetectable breaks of the blinding.
p.000028: 5.13.5 If significant formulation changes are made in the investigational or comparator
p.000028: product(s) during the course of clinical development, the results of any additional studies of the
p.000028: formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether
p.000028: these changes would significantly alter the pharmacokinetic profile of the product should be
p.000028: available prior to the use of the new formulation in clinical trials.
p.000028:
p.000028: 5.14 Supplying and Ha ndling Inves tigatio nal P roduct( s)
p.000028: 5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the
p.000028: investigational product(s).
p.000028: 5.14.2 The sponsor should not supply an investigator/institution with the inves tigational
p.000028: product(s) until the sponsor obtains all required documentation (e.g. approval/favourable opinion
p.000028: from IRB/IEC and regulatory authority(ies)).
p.000028: 5.14.3 The sponsor should ensure that written procedures include instructions that the
p.000028: investigator/institution should follow for the handling and storage of inves tigational
p.000028: product(s) for the trial and documentation thereof. The procedures should address adequate and safe
p.000028: receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of
p.000028: unused investigational product(s) to the sponsor (or alternative disposition i f authorised by the
p.000028: sponsor and in compliance with the applicable regulatory requirement(s)).
p.000028: 5.14.4 The sponsor should:
p.000028: a) Ensure timely delivery of investigational product(s) to the investigator(s).
p.000028: b) Maintain records that document shipment, receipt, disposition, return, and destruction of the
p.000028: investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical T r i a
p.000028: l).
p.000028: c ) Maintain a system for retrieving investigational products and documenting this
p.000028: retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product
p.000028: reclaim).
p.000028: d) Maintain a system for the disposition of unused investigational product(s) and for the
p.000028: documentation of this disposition.
p.000028: 5.14.5 The sponsor should:
p.000028: a) Take steps to ensure that the investigational product(s) are stable over the period of use.
p.000028: b) Maintain sufficient quantities of the investigational product(s) used in the trials to
p.000028: reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and
p.000028: characteristics. To the extent stability permits, samples should be
p.000028: retained either until the analyses of the trial data are complete or as required by the applicable
p.000028: regulatory requirement(s), whichever represents the longer retention period.
p.000028:
p.000028: 5.15 R ecord Access
p.000028: 5.15.1 The sponsor should ensure that it is specified in the protocol or other written
p.000028: agreement that the investigator(s)/institution(s) provide direct access to
p.000028: source
p.000028:
p.000028:
p.000029: 29
p.000029:
p.000029: ■ 3CC1a _____________________________________________________________
p.000029:
p.000029:
p.000029:
p.000029: data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory
p.000029: inspection.
p.000029: 5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to
p.000029: his/her original medical records for trial-related monitoring, audit, IRB/IEC review, a nd regulatory
p.000029: inspection.
p.000029:
p.000029: 5.16 Safe ty Informa tio n
p.000029: 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the inves tigational
p.000029: product(s).
p.000029: 5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) a nd the
p.000029: regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact
p.000029: the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial.
p.000029:
p.000029: 5.17 Adverse Drug Reaction Reporting
p.000029: 5.17.1 The sponsor should expedite the reporting to all
p.000029: conce rn ed investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the
p.000029: regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected.
p.000029: 5.17.2 Such expedited reports should co mply with the applicable regulatory requir ement(s) and with
p.000029: the note for guidance on Clinical Safety Data Management: Definitions and Standards for
p.000029: Expedited Reporting .
p.000029: 5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates a nd
p.000029: periodic reports, as required by applicable regulatory requirement(s).
p.000029:
p.000029: 5.18 Monito ri ng
p.000029: 5.18.1 Purpose
p.000029: The purposes of trial monitoring are to verify that:
p.000029: a) The rights and well-being of human subjects are protected.
p.000029: b) The reported trial data are accurate, complete, and verifiable from source documents.
p.000029: c ) The conduct of the trial is in compliance with the currently
p.000029: approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
p.000029:
p.000029: 5.18.2 Selection a n d Qualifica tions of Monitors
p.000029: a) Monitors should be appointed by the sponsor.
p.000029: b) Monitors should be appropriately trained, and should have the scientific and/or
p.000029: clinical knowledge needed to monitor the trial adequately. A monitor’s q ualification s should be
p.000029: documented.
p.000029: c ) Monitors should be thoroughly familiar with the investigational product(s), the
p.000029: protocol, written informed consent form and any other written information to be provided
p.000029: to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
p.000029:
p.000029:
p.000030: 30
p.000030:
p.000030: _____________________________________________________________ 3CC1a ■
p.000030:
p.000030:
p.000030:
p.000030: 5.18.3 Extent a n d N a ture of Monitoring
p.000030: The sponsor should ensure that the trials are adequately monitored. The sponsor should
...
p.000032: :
p.000032:
p.000032: 5.19.1 Purpose
p.000032: The purpose of a sponsor’s audit, which is independent of and separate from routine
p.000032: monitoring or quality control functions, should be to evaluate trial conduct and com pli ance with the
p.000032: protocol, SOPs, GCP, and the applicable regulatory requirements.
p.000032:
p.000032: 5.19.2 Selection and Qualification of Auditors
p.000032: a) The sponsor should appoint individuals, who are independent of the cli n ic a
p.000032: l trials/systems, to conduct audits.
p.000032: b) The sponsor should ensure that the auditors are qualified by training and experience to conduct
p.000032: audits properly. An auditor’s qualifications should be documented.
p.000032:
p.000032: 5.19.3 Au d iting Proced ures
p.000032: a) The sponsor should ensure that the audi t ing of clinical trials/systems is conducted i n
p.000032: accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of
p.000032: audits, and the form and content of audit reports.
p.000032: b) The sponsor's audit plan and procedures for a trial audit should be guided by the
p.000032: importance of the trial to submissions to regulatory authorities, the number of subjects in the trial,
p.000032: the type and complexity of the trial, the level of risks to the trial subjects, and any identified
p.000032: problem(s).
p.000032: c ) The observations and findings of the auditor(s) should be documented.
p.000032: d) To preserve the independence and value of the audit function, the regulatory
p.000032: authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek
p.000032: access to an audit report on a case by case basis when evidence of se r iou s GCP non-compliance
p.000032: exists, or in the course of legal proceedings.
p.000032: e) When required by applicable law or regulation, the sponsor should provide an audit
p.000032: certificate.
p.000032:
p.000033: 33
p.000033:
p.000033: ■ 3CC1a _____________________________________________________________
p.000033:
p.000033:
p.000033:
p.000033:
p.000033: 5.20 Noncomp li ance
p.000033: 5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory
p.000033: requirement(s) by an investigator/institution, or by member(s) of the sponsor’s staff should lead to
p.000033: prompt action by the sponsor to secure compliance.
p.000033: 5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part
p.000033: of an investigator/institution, the sponsor should terminate the inves tigator’s/ institution’s
p.000033: participation in the trial. When an investigator’s/institution’s participation i s
p.000033: terminated because of noncompliance, the sponsor should notify promptly the regulatory
p.000033: authority(ies).
p.000033:
p.000033: 5.21 Premature Termination or Suspension of a Trial
p.000033: If a trial is prematurely terminated or suspended, the sponsor should promptly inform the
p.000033: investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the
p.000033: reason(s) for the termination or suspension. The IRB/IEC should also be i nform ed promptly and provided
p.000033: the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as
p.000033: specified by the applicable regulatory requirement(s).
p.000033:
p.000033: 5.22 Cli n ical Trial/Study R eports
p.000033: Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical
p.000033: trial reports are prepared and provided to the regulatory agency(ies) as r equired by the applicable
p.000033: regulatory requirement(s). The sponsor should also ensure that the cli n ic a l trial reports in
p.000033: marketing applications meet the standards of the note for guidance o n Structure and Content of
p.000033: Clinical S tudy Reports . (NOTE: The note for guidance on S tructure and Content of Clinical S
p.000033: tudy Reports specifies that abbreviated study reports may be acceptable in certain cases.)
p.000033:
p.000033: 5.23 Multicentre Trials
p.000033: For multicentre trials, the sponsor should ensure that:
p.000033: 5.23.1 All investigators conduct the trial in strict compliance with the protocol agreed to by the
p.000033: sponsor and, if required, by the regulatory authority(ies), and gi ven approval/favourable opinion by the
p.000033: IRB/IEC.
p.000033: 5.23.2 The CRFs are designed to capture the required data at all multicentre trial sites. For
p.000033: those investigators who are collecting additional data, supplemental CRFs should also be provided
p.000033: that are designed to capture the additional data.
p.000033: 5.23.3 The responsibilities of co-ordinating investigator(s) and the other partici pating
p.000033: investigators are documented prior to the start of the trial.
p.000033: 5.23.4 All investigators are given instructions on following the protocol, on complying with a
p.000033: uniform set of standards for the assessment of clinical and laboratory findings, and o n
p.000033: completing the CRFs.
p.000033: 5.23.5 Communication between investigators is facilitated.
p.000033:
p.000033:
p.000033:
p.000033:
p.000034: 34
p.000034:
p.000034: _____________________________________________________________ 3CC1a ■
p.000034:
p.000034:
p.000034:
p.000034: 6. CLINICAL TRIAL P ROTOCOL AND P ROTOCOL AMENDMENT( S)
p.000034: The contents of a trial protocol should generally include the following topics. However, site
p.000034: specific information may be provided on separate protocol page(s), or addressed in a separate
p.000034: agreement, and some of the information listed below may be contained in other protocol
p.000034: referenced documents, such as an Investigator’s Brochure.
p.000034:
p.000034: 6.1 General Informa tio n
p.000034: 6.1.1 Protocol title, protocol identifying number, and date. Any amendment(s) should a l so bear the
p.000034: amendment number(s) and date(s).
...
p.000044: 6.2 Safety and Efficacy
p.000044: 6.3 Marketing Experience
p.000044: 7. Summary of Data and Guidance for the Investigator
p.000044:
p.000044: NB: References on 1. Publications
p.000044: 2. Reports
p.000044: These references should be found at the end of each chapter Appendices (if any)
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000044:
p.000045: 45
p.000045:
p.000045: ■ 3CC1a _____________________________________________________________
p.000045:
p.000045:
p.000045:
p.000045: 8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
p.000045: 8.1 I n trod uc tio n
p.000045: Essential Documents are those documents which in divid ually and collectively permit
p.000045: evaluation of the conduct of a trial and the quality of the data produced. These documents serve
p.000045: to demonstrate the compliance of the investigator, sponsor and monitor with the standards of
p.000045: Good Clinical Practice and with all applicable regulatory requirements.
p.000045: Essential Documents also serve a number of other important purposes. Filing essential
p.000045: documents at the investigator/institution and sponsor sites in a t imely manner can greatly assist
p.000045: in the successful management of a trial by the investigator, sponsor and monitor. These
p.000045: documents are also the ones which are usually audited by the sponsor's independent audit function
p.000045: and inspected by the regulatory authority (ies) as part of the process to confirm
p.000045: the validity of the trial conduct and the integrity of data collected.
p.000045: The mini mum lis t of essential documents which has been developed follows. The variou s documents
p.000045: are grouped in three sections according to the stage of the trial during which they will normally
p.000045: be generated: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of
p.000045: the trial, and 3) after completion or termination of the trial. A description is given of the
p.000045: purpose of each document, and whether it should be filed in either the
p.000045: investigator/institution or sponsor files, or both. It is acceptable to combine some of the
p.000045: documents, provided the individual elements are readily identifiable.
p.000045: Trial master files should be established at the beginning of the trial, both at
p.000045: the investigator/institution’s site and at the sponsor’s office. A final close-out of a trial can o n
p.000045: ly be done when the monitor has reviewed both investigator/institution and sponsor files a nd
p.000045: confirmed that all necessary documents are in the appropriate files.
p.000045: Any or all of the documents addressed in this guideline may be subject to, and should be
p.000045: available for, audit by the sponsor’s auditor and inspection by the regulatory authority(ies).
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000046: 46
p.000046:
p.000046: _____________________________________________________________ 3CC1a ■
p.000046:
p.000046:
p.000046:
p.000046: 8.2 Before the Clinical Ph ase of the Trial Commences
p.000046: During this planning stage the following documents should be generated and should be o n file before
p.000046: the trial formally starts
p.000046:
p.000046: Titl e of Document Pu rpose
p.000046: Located i n Files of
p.000046:
p.000046: Investigator/ I ns tit u tio n
p.000046: Sponso r
p.000046: 8.2.1 INVESTIGATOR’S BROCHURE To document that relevant and X
p.000046: X
p.000046: current scientific information
p.000046: about the investigational product has been provided to the
p.000046: investigator
p.000046:
p.000046: 8.2.2 SIGNED PROTOCOL AND
p.000046: AMENDMENTS, IF ANY, AND SAMPLE CASE RE PORT FORM (C RF )
p.000046: 8.2.3 INFORMATION GIVEN TO TRIAL SUB J ECT
p.000046: – INFORMED CONSENT FORM
p.000046: (including all applicable tran slation s)
p.000046: – ANY OTHER WRITTEN INFORMATION
p.000046:
p.000046:
p.000046:
p.000046: – ADVERTISEMENT FOR
p.000046: SUB J ECT RECRUITMENT (if
p.000046: used)
p.000046: 8.2.4 FINANCIAL AS P ECTS OF THE TRIAL
p.000046:
p.000046:
p.000046: 8.2.5 INSURANCE STATEMENT
p.000046: (where required)
p.000046:
p.000046:
p.000046: 8.2.6 SIGNED AGREEMENT BETWEEN INVOLVED PARTIES , e.g.:
p.000046: – investigator/institution and sponsor
p.000046: – investigator/institution and CRO
p.000046: – sponsor and CRO
p.000046: – investigator/institution and
p.000046: authority(ies) (where required)
p.000046: To document investigator and X X sponsor agreement to the
p.000046: protocol/amendment(s) and CRF
p.000046:
p.000046:
p.000046:
p.000046: To document the informed X X consent
p.000046:
p.000046:
p.000046: To document that subjects will be X X given appropriate
p.000046: written
p.000046: information (content and
p.000046: wording) to support their ability to give fully informed consent
p.000046: To document that recruitment X measures are appropriate and not
p.000046: coe rcive
p.000046: To document the financial X X agreement between the
p.000046: investigator/institution and the sponsor for the trial
p.000046: To document that compensation to X X subject(s) for trial-related
p.000046: injury
p.000046: will be available
p.000046: To document agreements
p.000046:
p.000046: X X
p.000046: X
p.000046: X (where
p.000046: required) X
p.000046: X X
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000047: 47
p.000047:
p.000047: ■ 3CC1a _____________________________________________________________
p.000047:
p.000047:
p.000047:
p.000047:
p.000047: Titl e of Document Pu rpose
p.000047: Located i n Files of
p.000047:
p.000047: Investigator/ I ns tit u tio n
p.000047: Sponso r
p.000047:
...
p.000047: – CRF (if applicable)
p.000047: – informed consent form(s)
p.000047: – any other written information to be provided to the subject(s)
p.000047: – advertisement for subject recruitment (if used)
p.000047: – subject compensation (if any)
p.000047: – any other documents given
p.000047: approval/ favourable opinion
p.000047: 8.2.8 INSTITUTIONAL REVIEW
p.000047: BOARD/INDE P ENDENT ETHICS COMMITTEE COMPOSITION
p.000047: To document that the trial has been subject to IRB/IEC review and given approval/favourable
p.000047: opinion. To identify the version number and date of the
p.000047: document(s)
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047: To document that the IRB/IEC is constituted in agreement with GCP
p.000047: X X
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047: X X
p.000047: (where required)
p.000047:
p.000047: 8.2.9 REGULATORY
p.000047: AU THORITY(IES)
p.000047: AUTHORISATION/ A PP ROVAL/ NOTIFICATION OF P ROTOCOL
p.000047: (where required)
p.000047: To document appropriate authorisation/approval/
p.000047: notification by the regulatory
p.000047: authority(ies) has been obtained prior to initiation of the trial in compliance with the applicable
p.000047: regulatory requirement(s)
p.000047: X
p.000047: (where required)
p.000047: X
p.000047: (where required)
p.000047:
p.000047: 8.2.10 CURRICULUM VITAE AND/OR OTHER RELEVANT
p.000047: DOCUMENTS EVIDENCING QUALIFICATIONS OF
p.000047: INVESTIGATOR( S) AND SUB- INVESTIGATOR( S)
p.000047: 8.2.11 NORMAL VALUE( S)/ RANGE( S) FOR MEDICAL/
p.000047: LA B ORATORY/TECHNICAL P ROCEDURE( S) AND/OR
p.000047: TEST( S) INCLUDED IN THE PROTOCOL
p.000047: To document qualifications and X X eligibility to conduct
p.000047: trial and/or
p.000047: provide medical supervision of subjects
p.000047:
p.000047:
p.000047: To document normal values X X and/or ranges of the
p.000047: tests
p.000047:
p.000047: 8.2.12 MED ICAL/ LA B O RATORY/ TECHNICAL P ROCEDURES/ TESTS
p.000047: – certification or
p.000047: – accreditation or
p.000047: – established quality control and/or external quality
p.000047: assessment or
p.000047: – other validation (where required)
p.000047: To document competence of facility to perform required
p.000047: test(s), and support reliability of results
p.000047: X X
p.000047: (where required)
p.000047:
p.000047:
p.000048: 48
p.000048:
p.000048: _____________________________________________________________ 3CC1a ■
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: Titl e of Document Pu rpose
p.000048:
p.000048: Located i n Files of
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: 8.2.13 SAMPLE OF LABEL( S) ATTACHED TO
...
p.000050: subject and substantiate integrity of trial data collected. To include original documents related to the
p.000050: trial, to medical treatment, and
p.000050: history of subject
p.000050:
p.000050: 8.3.14 SIGNED, DATED AND
p.000050: COMPLETED CASE RE PORT FORMS (CRF)
p.000050: To document that the investigator or authorised member of the
p.000050: investigator’s staff confirms the observations recorded
p.000050: X
p.000050: (copy)
p.000050: X
p.000050: (or igi na l)
p.000050:
p.000050:
p.000050:
p.000050:
p.000051: 51
p.000051:
p.000051: ■ 3CC1a _____________________________________________________________
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: Titl e of Document Pu rpose
p.000051: Located i n Files of
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: 8.3.15 DOCUMENTATION OF CRF CORRECTIONS
p.000051:
p.000051:
p.000051:
p.000051: To document all changes/
p.000051: additions or corrections made to CRF after initial data were
p.000051: recorded
p.000051: Investigator/ I ns tit u tio n
p.000051: X
p.000051: (copy)
p.000051: Sponso r
p.000051:
p.000051:
p.000051: X
p.000051: (or igi na l)
p.000051:
p.000051: 8.3.16 NOTIFICATION BY
p.000051: ORIGINATING INVESTIGATOR TO S PONSOR OF SERIOUS
p.000051: ADVERSE EVENTS AND RELATED REPORTS
p.000051: Notification by originating X X investigator to
p.000051: sponsor of serious
p.000051: adverse events and related reports in accordance with 4.11
p.000051:
p.000051: 8.3.17 NOTIFICATION BY S PONSOR AND/OR INVESTIGATOR,
p.000051: WHERE APPLICABLE, TO REGULATORY
p.000051: AUTHORITY(IES) AND
p.000051: IRB( S)/IEC( S) OF UNEXP ECTED SERIOUS ADVERSE DRUG
p.000051: REACTIONS AND OF OTHER SAFETY INFORMATION
p.000051: Notification by sponsor and/or
p.000051: investigator, where applicable, to regulatory authorities and
p.000051: IRB(s)/IEC(s) of unexpected
p.000051: serious adverse drug reactions in accordance with 5.17 and 4.11.1
p.000051: and of other safety information in accordance with 5.16.2
p.000051: X X
p.000051: (where required)
p.000051:
p.000051: 8.3.18 NOTIFICATION BY S PONSOR TO INVESTIGATORS OF SAFETY
p.000051: INFORMATION
p.000051:
p.000051:
p.000051: 8.3.19 INTERIM OR ANNUAL
p.000051: RE PORTS TO IRB/IEC AND AU THORITY(IES)
p.000051: Notification by sponsor to investigators of safety
p.000051: information in accordance with 5.16.2
p.000051: Interim or annual reports provided to IRB/IEC in
p.000051: accordance with 4.10 and to
p.000051: authority(ies) in accordance with 5.17.3
p.000051: X X
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: X X
p.000051: (where required)
p.000051:
p.000051: 8.3.20 SUB JECT SCREENING LOG To document identification of
p.000051: subjects who entered pre-trial scr ee n i n g
p.000051: X X
p.000051: (where required)
p.000051:
p.000051: 8.3.21 SUB J ECT IDENTIFICATION CODE LIST
p.000051: To document that X
p.000051: investigator/institution keeps a confidential lis t of names of all
p.000051: subjects allocated to trial numbers on enrolling in the trial. Allows
p.000051: investigator/institution to reveal identity of any subject
p.000051: 8.3.22 SUB J ECT ENROLMENT LOG To document chronological X
p.000051: enrolment of subjects by trial number
p.000051:
p.000051: 8.3.23 INVESTIGATIONAL P RODUCTS ACCOUNTABILITY AT THE SITE
p.000051: To document that investigational X X product(s) have been used
p.000051: according to the protocol
p.000051: 8.3.24 SIGNATURE SHEET To document signatures and
p.000051: X X
p.000051: initials of all persons authorised to make entries and/or
p.000051: corrections on CRFs
p.000051:
p.000051: 8.3.25 RECORD OF RETAINED BODY FLUIDS/ TISSUE SAMPLES (IF A N Y )
p.000051: To document location and X X identification of
p.000051: retained samples
p.000051: if assays need to be repeated
p.000051:
p.000051:
p.000051:
p.000052: 52
p.000052:
...
General/Other / participants in a control group
Searching for indicator placebo:
(return to top)
p.000005: being unaware of the treatment assignment(s).
p.000005:
p.000005: 1.11 Case Report Form (CRF)
p.000005: A printed, optical, or electronic document designed to record all of the protocol required
p.000005: information to be reported to the sponsor on each trial subject.
p.000005:
p.000005:
p.000005:
p.000005:
p.000005:
p.000005:
p.000006: 6
p.000006:
p.000006: _____________________________________________________________ 3CC1a ■
p.000006:
p.000006:
p.000006:
p.000006: 1.12 Cli n ical Trial/Study
p.000006: Any investigation in human subjects intended to discover or verify the cli n ic a
p.000006: l, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to
p.000006: identify any adverse reactions to an investigational product(s), and/or to study absorption,
p.000006: distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining
p.000006: its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.
p.000006:
p.000006: 1.13 Cli n ical Trial/Study R eport
p.000006: A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted
p.000006: in human subjects, in which the clinical and statistical description, presentations, and analyses are
p.000006: fully integrated into a single report (see note for guidance on S tructure and Content of Clinical
p.000006: S tudy Reports ).
p.000006:
p.000006: 1.14 Comparator ( P roduct)
p.000006: An investigational or marketed product (i.e., active control), or placebo, used as a r efe r e nce in
p.000006: a clinical trial.
p.000006:
p.000006: 1.15 Compliance ( in relation to trials)
p.000006: Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirement s, and the
p.000006: applicable regulatory requirements.
p.000006:
p.000006: 1.16 Confid en tiality
p.000006: Prevention of disclosure, to other than authorised individuals, of a sponsor's proprietary
p.000006: information or of a subject’s identity.
p.000006:
p.000006: 1.17 Contract
p.000006: A written, dated, and signed agreement between two or more involved parties that sets out any
p.000006: arrangements on delegation and distribution of tasks and obligations and, i f
p.000006: appropriate, on financial matters. The protocol may serve as the basis of a contract.
p.000006:
p.000006: 1.18 Co-ordinating Committee
p.000006: A committee that a sponsor may organise to co-ordinate the conduct of a multicentre trial.
p.000006:
p.000006:
p.000006: 1.19 Co-ordinating Investigator
p.000006: An investigator assigned the responsibility for the co-ordination of investigators at different centres
p.000006: participating in a multicentre trial.
p.000006:
p.000006: 1.20 Contract Research Organisation (CRO)
p.000006: A person or an organisation (commercial, academic, or other) contracted by the sponsor to perform
p.000006: one or more of a sponsor’s trial-related duties and functions.
p.000006:
p.000007: 7
p.000007:
p.000007: ■ 3CC1a _____________________________________________________________
p.000007:
p.000007:
p.000007:
p.000007: 1.21 Direct Access
...
p.000008: facilities, records, and any other resources that are deemed by the authority(ies) to be related to
p.000008: the clinical trial and that may be l ocated at the site of the trial, at the sponsor’s and/or
p.000008: contract research org anisation’s (CRO’s) facilities, or at other establishments dee med
p.000008: appropriate by the regulatory authority(ies).
p.000008:
p.000008: 1.30 Ins tit u tio n ( med ical)
p.000008: Any public or private entity or agency or medical or dental facility where clinical trials are
p.000008: conducted.
p.000008:
p.000008: 1.31 Institutional Revie w Board (IRB)
p.000008: An independent body constituted of medical, scientific, and non-scientific members, whose
p.000008: responsibility is to ensure the protection of the rights, safety and well-being of human
p.000008: subjects involved in a trial by, among other things, reviewing, approving, and p roviding
p.000008: continuing review of trial protocol and amendments and of the methods and material to be used in
p.000008: obtaining and documenting informed consent of the trial subjects.
p.000008:
p.000008: 1.32 Int erim Clinical Trial/Study Report
p.000008: A report of intermediate results and their evaluation based on analyses performed d ur i n g the
p.000008: course of a trial.
p.000008:
p.000008: 1.33 Inves tigatio nal P roduct
p.000008: A pharmaceutical form of an active ingredient or placebo being tested or used as a r efe r e nce in
p.000008: a clinical trial, including a product with a marketing a uthorisation when used or
p.000008: assembled (formulated or packaged) in a way different from the a pproved form, or when used for
p.000008: an unapproved indic ation, or when used to gain further information about a n approved use.
p.000008:
p.000008:
p.000008:
p.000008:
p.000008:
p.000009: 9
p.000009:
p.000009: ■ 3CC1a _____________________________________________________________
p.000009:
p.000009:
p.000009:
p.000009: 1.34 Investigator
p.000009: A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted
p.000009: by a team of individuals at a trial site, the investigator is the responsible leader of the team
p.000009: and may be called the principal investigator. See also Subinvestigator.
p.000009:
p.000009: 1.35 Investigator / Institution
p.000009: An expression meaning “the investigator and/or institution, where required by the
p.000009: applicable regulatory requirements”.
p.000009:
p.000009: 1.36 Investigator’s Brochure
p.000009: A compilation of the clinical and nonclinical data on the investigational product(s) which i s relevant
p.000009: to the study of the investigational product(s) in human subjects (see 7. Investigator’s Brochure).
p.000009:
p.000009: 1.37 Legally Acceptable Representative
p.000009: An individual or juridical or other body authorised under applicable law to consent, o n behalf
p.000009: of a prospective subject, to the subject’s participation in the clinical trial.
p.000009:
p.000009: 1.38 Monito ri ng
...
p.000027: of the trial, such as modification(s) of the protocol, written informed consent form a nd any other
p.000027: written information to be provided to subjects, and/or other procedures, the sponsor should obtain from
p.000027: the investigator/institution a copy of the modification(s) made and the date approval/favourable
p.000027: opinion was given by the IRB/IEC.
p.000027: 5.11.3 The sponsor should obtain from the investigator/institution documentation and dates of any
p.000027: IRB/IEC reapprovals/re-evaluations with favourable opinion, and of any with drawals or suspensions of
p.000027: approval/favourable opinion.
p.000027:
p.000027: 5.12 Informa tio n on Inves tigatio nal P roduct( s)
p.000027: 5.12.1 When planning trials, the sponsor should ensure that s ufficient safety and efficacy data
p.000027: from nonclinical studies and/or clinical trials are available to support human exposure
p.000027: by the route, at the dosages, for the duration, and in the trial population to be studied.
p.000027: 5.12.2 The sponsor should update the Investigator’s Brochure as significant new
p.000027: information becomes available (see 7. Investigator's Brochure).
p.000027:
p.000027: 5.13 Manufacturing, P ackaging, Labelling, and Coding Inves tigatio nal P roduct( s)
p.000027: 5.13.1 The sponsor should ensure that the investigational product(s) (inclu ding active
p.000027: comparator(s) and placebo, if applicable) is characterised as appropriate to the stage of
p.000027: development of the product(s), is manufactured in accordance with any applicable GMP, a nd
p.000027: is coded and labelled in a manner that protects the blinding, if applicable. In addition, the
p.000027: labelling should comply with applicable regulatory requirement(s).
p.000027: 5.13.2 The sponsor should determine, for the investigational product(s), acceptable s torage
p.000027: temperatures, storage conditions (e.g. protection from light), s torage times, reconstitution fluids
p.000027: and procedures, and devices for product infusion, if any. The sponsor should i n fo rm all involved
p.000027: parties (e.g. monitors, investigators, pharmacists, s torage managers) of these de t ermination s.
p.000027: 5.13.3 The investigational product(s) should be packaged to prevent contamination a nd
p.000027: unacceptable deterioration during transport and s torage.
p.000027:
p.000028: 28
p.000028:
p.000028: _____________________________________________________________ 3CC1a ■
p.000028:
p.000028:
p.000028:
p.000028: 5.13.4 In blinded trials, the coding system for the investigational product(s) should i ncl u de a
p.000028: mechanism that permits rapid identification of the product(s) in case of a m edica l
p.000028: emergency, but does not permit undetectable breaks of the blinding.
p.000028: 5.13.5 If significant formulation changes are made in the investigational or comparator
p.000028: product(s) during the course of clinical development, the results of any additional studies of the
...
p.000034: 6.2.2 A s ummary of findings from nonclinical studies that potentially have cli n ic a l
p.000034: significance and from clinical trials that are relevant to the trial.
p.000034: 6.2.3 Summary of the known and potential risks and benefits, if any, to human subjects.
p.000034: 6.2.4 Description of, and justification for, the route of administration, dosage, dos age
p.000034: regimen, and treatment period(s).
p.000034: 6.2.5 A statement that the trial will be conducted in compliance with the protocol, GCP a nd the
p.000034: applicable regulatory requirement(s).
p.000034: 6.2.6 Description of the population to be studied.
p.000034: 6.2.7 References to literature and data that are relevant to the trial, and that
p.000034: provide background for the trial.
p.000034:
p.000034: 6.3 Trial Objectives and Purpose
p.000034: A detailed description of the objectives and the purpose of the trial.
p.000034:
p.000034:
p.000034:
p.000034:
p.000035: 35
p.000035:
p.000035: ■ 3CC1a _____________________________________________________________
p.000035:
p.000035:
p.000035:
p.000035: 6.4 Trial Design
p.000035: The scientific integrity of the trial and the credibility of the data from the trial depend
p.000035: substantially on the trial design. A description of the trial design, should include:
p.000035: 6.4.1 A specific statement of the primary endpoints and the secondary endpoints, if any, to be
p.000035: measured during the trial.
p.000035: 6.4.2 A description of the type/design of trial to be conducted (e.g. double-blind, placebo-
p.000035: controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
p.000035: 6.4.3 A description of the measures taken to minimise/avoid bias, including: a) R an domis ation.
p.000035: b) Bli n d i n g.
p.000035: 6.4.4 A description of the trial treatment(s) and the dosage and dosage regimen of the
p.000035: investigational product(s). Also include a description of the dosage form, packaging, a nd labelling
p.000035: of the investigational product(s).
p.000035: 6.4.5 The expected duration of subject participation, and a description of the sequence a nd
p.000035: duration of all trial periods, including follow-up, if any.
p.000035: 6.4.6 A description of the “stopping rules” or “discontinuation criteria” for i n divid ua l
p.000035: subjects, parts of trial and entire trial.
p.000035: 6.4.7 Accountability procedures for the investigational product(s), including the placebo(s) and
p.000035: comparator(s), if any.
p.000035: 6.4.8 Maintenance of trial treatment randomisation codes and procedures for b r e ak i n g
p.000035: codes.
p.000035: 6.4.9 The identification of any data to be recorded directly on the CRFs (i.e. no
p.000035: prior written or electronic record of data), and to be considered to be source data.
p.000035:
p.000035: 6.5 Selec tion and Withdra w al of Subjec ts
p.000035: 6.5.1 S ubject inclusion criteria.
p.000035: 6.5.2 Subject exclusion criteria.
p.000035: 6.5.3 Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment)
p.000035: and procedures specifying:
p.000035: a) When and how to withdraw subjects from the trial/ investigational product treatment.
p.000035: b) The type and timing of the data to be collected for withdrawn subjects. c ) Whether and
p.000035: how subjects are to be replaced.
p.000035: d) The follow-up for subjects withdrawn from investigational product treatment/trial
p.000035: treatment.
p.000035:
p.000035: 6.6 Treatment of Subjects
p.000035: 6.6.1 The treatment(s) to be administered, including the name(s) of all the product(s), the
p.000035: dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment
p.000035: period(s), including the follow-up period(s) for subjects for each investigational product
p.000035: treatment/trial treatment group/arm of the trial.
p.000035:
p.000036: 36
p.000036:
p.000036: _____________________________________________________________ 3CC1a ■
p.000036:
p.000036:
p.000036:
...
Orphaned Trigger Words
p.000019: investigator, should provide the subject or the subject's legally acceptable representative ample time
p.000019: and opportunity to inquire about details of the trial and to decide whether or not to
p.000019: participate in the trial. All questions about the trial should be answered to the satisfaction of
p.000019: the subject or the subject's legally acceptable representative.
p.000019: 4.8.8 Prior to a subject’s participation in the trial, the written informed consent fo rm
p.000019: should be signed and personally dated by the subject or by the subject's legally acceptable
p.000019: representative, and by the person who conducted the informed consent discussion.
p.000019: 4.8.9 If a subject is unable to read or if a legally acceptable representative is unable
p.000019: to read, an impartial witness should be present during the entire informed consent discu ssion. After
p.000019: the written informed consent form and any other written information to be provided to subjects, is
p.000019: read and explained to the subject or the subject’s legally acceptable
p.000019: representative, and after the subject or the subject’s legally acceptable representative has
p.000019: orally consented to the subject’s participation in the trial and, if capable of doing so, has
p.000019: signed and personally dated the informed consent form, the witness should sign a nd
p.000019: personally date the consent form. By signing the consent form, the witness attests that the
p.000019: information in the consent form and any other written information was accurately
p.000019: explained to, and apparently understood by, the subject or the subject's legally acceptable
p.000019: representative, and that informed consent was freely given by the subject or the subject’s
p.000019: legally acceptable representative.
p.000019: 4.8.10 Both the informed consent discussion and the written informed consent form a nd any
p.000019: other written information to be provided to subjects should include explanations of the followi n g:
p.000019:
p.000020: 20
p.000020:
p.000020: _____________________________________________________________ 3CC1a ■
p.000020:
p.000020:
p.000020:
p.000020: a) That the trial involves research.
p.000020: b) The purpose of the trial.
p.000020: c ) The trial treatment(s) and the probability for random assignment to each treatment. d) The
p.000020: trial procedures to be followed, including all invasive procedures.
p.000020: e) The subject's responsibilities.
p.000020: f ) Those aspects of the trial that are experimental.
p.000020: g ) The reasonably foreseeable r isks or inconveniences to the subject and, when
...
p.000020: extent permitted by the applicable laws and/or regulations, will not be made p ublicly
p.000020: available. If the results of the trial are published, the subject’s identity will r e ma i n
p.000020: confide ntial.
p.000020: p) That the subject or the subject's legally acceptable representative will be informed in a t
p.000020: imely manner if information becomes available that may be relevant to the s ubject's willingness to
p.000020: continue participation in the trial.
p.000020: q) The person(s) to contact for further information regarding the trial and the rights of
p.000020: trial subjects, and whom to contact in the event of trial-related injury.
p.000020: r ) The foreseeable circumstances and/or reasons under which the subject's participation in the
p.000020: trial may be terminated.
p.000020: s) The expected duration of the subject's participation in the trial.
p.000020: t) The approximate number of subjects involved in the trial.
p.000020: 4.8.11 Prior to participation in the trial, the subject or the subject's legally
p.000020: acceptable representative should receive a copy of the signed and dated written informed consent fo
p.000020: rm and any other written information provided to the su bjects. During a subject’s participation
p.000020:
p.000021: 21
p.000021:
p.000021: ■ 3CC1a _____________________________________________________________
p.000021:
p.000021:
p.000021:
p.000021: in the trial, the subject or the subject’s legally acceptable representative should receive a copy of
p.000021: the signed and dated consent form updates and a copy of any amendments to the written information
p.000021: provided to subjects.
p.000021: 4.8.12 When a clinical trial (therapeutic or non-therapeutic) includes subjects who can o n ly be
p.000021: enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g., minors,
p.000021: or patients with severe dementia), the subject should be informed about the trial to the extent
p.000021: compatible with the subject’s understanding and, if capable, the subject should sign and personally date
p.000021: the written informed consent.
p.000021: 4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e. a trial in which there is no
p.000021: anticipated direct clinical benefit to the subject), should be conducted in subjects who
p.000021: personally give consent and who sign and date the written informed consent form.
p.000021: 4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a leg a lly
p.000021: acceptable representative provided the following conditions are fulfilled:
p.000021: a) The objectives of the trial can not be met by means of a trial in subjects who can give
p.000021: informed consent personally.
p.000021: b) The foreseeable risks to the subjects are low.
...
p.000030: trial and the trial site:
p.000030: a) Acting as the main line of communication between the sponsor and the investigator.
p.000030: b) Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2,
p.000030: 5.6) and remain adequate throughout the trial period, that facilities, i n cl u d i n g
p.000030: laboratories, equipment, and staff, are adequate to safely and properly conduct the tr i a l and remain
p.000030: adequate throughout the trial period.
p.000030: c ) Verifying, for the investigational product(s):
p.000030: i ) That storage times and conditions are acceptable, and that supplies are s ufficient
p.000030: throughout the trial.
p.000030: i i ) That the investigational product(s) are supplied only to subjects who are eligible to
p.000030: receive it and at the protocol specified dose(s).
p.000030: iii ) That subjects are provided with necessary instruction on properly u s i n g,
p.000030: handling, s toring, and returning the investigational product(s).
p.000030: i v) That the receipt, use, and return of the investigational product(s) at the trial sites are
p.000030: controlled and documented adequately.
p.000030: v ) That the dispo sition of unused investigational product(s) at the trial sites
p.000030: complies with applicable regulatory requirement(s) and is in accordance with the sponsor.
p.000030: d) Verifying that the investigator follows the approved protocol and all approved
p.000030: amendment(s), if any.
p.000030: e) Verifying that written informed consent was obtained before each s ubject's
p.000030: participation in the trial.
p.000030: f ) Ensuring that the investigator receives the current Investigator's Brochure, a l
p.000030: l documents, and all trial supplies needed to conduct the trial properly and to com ply with the
p.000030: applicable regulatory requirement(s).
p.000030: g ) Ensuring that the investigator and the investigator's trial staff are
p.000030: adequately informed about the trial.
p.000030: h) Verifying that the investigator and the investigator's trial staff are performing the
p.000030: specified trial functions, in accordance with the protocol and any other written
p.000030:
p.000031: 31
p.000031:
p.000031: ■ 3CC1a _____________________________________________________________
p.000031:
p.000031:
p.000031:
p.000031: agreement between the sponsor and the investigator/institution, and have not delegated these functions to
p.000031: unauthorised individuals.
p.000031: i ) Verifying that the investigator is enrolling only eligible subjects. j ) Reporting the
p.000031: subject recruitment rate.
p.000031: k ) Verifying that source documents and other trial records are accurate, complete, kept
p.000031: up-to-date and maintained.
p.000031: l) Verifying that the investigator provides all the r equired reports, notification
p.000031: s, applications, and submissions, and that these documents are accurate, complete, timely,
p.000031: legible, dated, and identify the trial.
p.000031: m ) Checking the accuracy and completeness of the CRF entries, source documents a nd other
...
p.000037:
p.000037:
p.000037: 6.13 Data Handling and Record Keeping
p.000037:
p.000037: 6.14 Financing and Insurance
p.000037: Financing and insurance if not addressed in a separate agreement.
p.000037:
p.000037:
p.000037: 6.15 Pu blication P olicy
p.000037: Publication policy, if not addressed in a separate agreement.
p.000037:
p.000037:
p.000037: 6.16 Supp l emen ts
p.000037: (NOTE: Since the protocol and the clinical trial/study report are closely related, further
p.000037: relevant information can be found in the note for guidance on Structure and Content o f
p.000037: Clinical S tudy Reports .)
p.000037:
p.000037:
p.000037: 7. INVESTIGATOR’S BROCHURE
p.000037: 7.1 I n trod uc tio n
p.000037: The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the
p.000037: investigational product(s) that are relevant to the study of the product(s) in human subjects. Its
p.000037: purpose is to provide the investigators and others involved in the trial with the
p.000037: information to facilitate their understanding of the rationale for, and their compliance with, many
p.000037: key features of the protocol, such as the dose, dose frequency/interval, methods of administration,
p.000037: and safety monitoring procedures. The IB also provides insight to support the clinical management
p.000037: of the study subjects during the course of the clinical trial. The information should be
p.000037: presented in a concise, simple, objective, balanced, and non- promotional form that enables
p.000037: a clinician, or potential investigator, to understand it a nd make his/her own unbiased
p.000037: risk/benefit assessment of the appropriateness of the proposed trial. For this reason, a medically
p.000037: qualified person should generally participate in the editing of an IB, but the contents
p.000037: of the IB should be approved by the disciplines that generated the described data.
p.000037: This guideline delineates the minimum information that should be included in an IB a nd provides
p.000037: suggestions for its layout. It is expected that the type and extent of i nformat ion available
p.000037: will vary with the stage of development of the investigational product. If the
p.000037: investigational product is marketed and its pharmacology is widely understood by m edica l
p.000037: practitioners, an extensive IB may not be necessary. Where permitted by regulatory
p.000037: authorities, a basic product information brochure, package leaflet, or la belling may be a n
p.000037: appropriate alternative, provided that it includes current, comprehensive, and detailed
p.000037: information on all aspects of the investigational product that might be of importance to the
p.000037: investigator. If a marketed product is being studied for a new use (i.e., a new indication), a n IB
p.000037: specific to that new use should be prepared. The IB should be reviewed at least annua lly and
p.000037: revised as necessary in compliance with a sponsor's written procedures. More frequent
p.000037:
p.000038: 38
p.000038:
p.000038: _____________________________________________________________ 3CC1a ■
p.000038:
p.000038:
p.000038:
p.000038: revision may be appropriate depending on the stage of development and the generation of relevant
p.000038: new information. However, in accord ance with Good Clinical Practice, relevant new information
p.000038: may be so important that it should be communicated to the investigators, and possibly to the
p.000038: Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and/or regulatory authorities
p.000038: before it is included in a revised IB.
p.000038: Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the
p.000038: investigator(s) and the investigators are responsible for providing the up-to-date IB to the responsible
p.000038: IRBs/IECs. In the case of an investigator sponsored trial, the sponsor- investigator
p.000038: should determine whether a brochure is available from the comm e r ci a l manufacturer. If
p.000038: the investigational product is provided by the sponsor-investigator, then he or she should provide
p.000038: the necessary information to the trial personnel. In cases where preparation of a formal IB
p.000038: is impractical, the sponsor-investigator should provide, as a substitute, an expanded background
p.000038: information section in the trial protocol that contains the minimum current information described in this
p.000038: guideline.
p.000038:
p.000038: 7.2 General Considerations
p.000038: The IB should include:
p.000038:
p.000038: 7.2.1 Title Page
p.000038: This should provide the sponsor’s name, the identity of each investigational product (i.e.,
p.000038: research number, chemical or approved generic name, and trade name(s) where leg a lly
p.000038: permissible and desired by the s ponsor), and the release date. It is also suggested that a n
p.000038: edition number, and a reference to the number and date of the edition it supersedes, be
p.000038: provided. An example is given in Appendix 1.
p.000038:
p.000038: 7.2.2 Confidenti a lity St a tement
...
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| access | Access to Social Goods |
| age | Age |
| authority | Relationship to Authority |
| coerce | Presence of Coercion |
| disability | Mentally Disabled |
| drug | Drug Usage |
| education | education |
| embryo | embryo |
| emergency | Public Emergency |
| employees | employees |
| ethnic | Ethnicity |
| foetus | Fetus/Neonate |
| gender | gender |
| hazard | Natural Hazards |
| homeless | Homeless Persons |
| illness | Physically Disabled |
| impaired | Cognitive Impairment |
| incapable | Mentally Incapacitated |
| incapacity | Incapacitated |
| infant | Infant |
| influence | Drug Usage |
| language | Linguistic Proficiency |
| minor | Youth/Minors |
| minority | Racial Minority |
| nomads | nomad |
| opinion | philosophical differences/differences of opinion |
| party | political affiliation |
| placebo | participants in a control group |
| single | Marital Status |
| substance | Drug Usage |
| terminal | Terminally Ill |
| unemployed | Unemployment |
| union | Trade Union Membership |
| volunteers | Healthy People |
| vulnerable | vulnerable |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| drug | ['influence', 'substance'] |
| influence | ['drug', 'substance'] |
| substance | ['drug', 'influence'] |
Trigger Words
coercion
consent
ethics
protect
protection
risk
volunteer
Applicable Type / Vulnerability / Indicator Overlay for this Input